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• W4289525431 abstract "The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This article provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This article focuses on clinical TPMT and NUDT15 PGx testing, which may be applied to all thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15)–related medications. These recommendations are not to be interpreted as prescriptive, but to provide a reference guide. The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This article provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This article focuses on clinical TPMT and NUDT15 PGx testing, which may be applied to all thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15)–related medications. These recommendations are not to be interpreted as prescriptive, but to provide a reference guide. Pharmacogenomic (PGx) testing has become an important tool to help clinicians select medications and prescribe an appropriate dose for certain patients. Several studies have documented the wide variation of alleles included in clinical PGx tests.1Pratt V.M. Everts R.E. Aggarwal P. Beyer B.N. Broeckel U. Epstein-Baak R. Hujsak P. Kornreich R. Liao J. Lorier R. Scott S.A. Smith C.H. Toji L.H. Turner A. Kalman L.V. Characterization of 137 genomic DNA reference materials for 28 pharmacogenetic genes: a GeT-RM collaborative project.J Mol Diagn. 2016; 18: 109-123Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar,2Moyer A.M. Vitek C.R.R. Giri J. Caraballo P.J. Challenges in ordering and interpreting pharmacogenomic tests in clinical practice.Am J Med. 2017; 130: 1342-1344Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Some tests are designed to detect many variant alleles in a PGx gene, whereas other tests interrogate only a limited number of alleles and may not include variants that are most relevant to clinical care. This can lead to a patient's genotype being reported as a ∗1 normal allele or no variants detected, even though clinically relevant variants may be present, which may cause discrepancies in interpretation, complicate advancement and implementation of PGx testing, and, ultimately, impact patient care. Until recently, there has been little effort to standardize the specific alleles that should be included in clinical PGx tests. To address this issue, the Association for Molecular Pathology (AMP) Pharmacogenomics (PGx) Working Group has developed a series of documents that recommend a minimum set of variant alleles to include in clinical PGx assays to facilitate standardization across laboratories and ensure that the most clinically relevant variant alleles are included in clinical PGx assays. The previously reported recommendations included CYP2C193Pratt V.M. Del Tredici A.L. Hachad H. Ji Y. Kalman L.V. Scott S.A. Weck K.E. Recommendations for clinical CYP2C19 genotyping allele selection: a report of the Association for Molecular Pathology.J Mol Diagn. 2018; 20: 269-276Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar and CYP2C9,4Pratt V.M. Cavallari L.H. Del Tredici A.L. Hachad H. Ji Y. Moyer A.M. Scott S.A. Whirl-Carrillo M. Weck K.E. Recommendations for clinical CYP2C9 genotyping allele selection: a joint recommendation of the Association for Molecular Pathology and College of American Pathologists.J Mol Diagn. 2019; 21: 746-755Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar genes important for warfarin PGx testing,5Pratt V.M. Cavallari L.H. Del Tredici A.L. Hachad H. Ji Y. Kalman L.V. Ly R.C. Moyer A.M. Scott S.A. Whirl-Carrillo M. Weck K.E. Recommendations for clinical warfarin genotyping allele selection: a report of the Association for Molecular Pathology and the College of American Pathologists.J Mol Diagn. 2020; 22: 847-859Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar and CYP2D6.6Pratt V.M. Cavallari L.H. Del Tredici A.L. Gaedigk A. Hachad H. Ji Y. Kalman L.V. Ly R.C. Moyer A.M. Scott S.A. van Schaik R.H.N. Whirl-Carrillo M. Weck K.E. Recommendations for clinical CYP2D6 genotyping allele selection: a joint consensus recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association.J Mol Diagn. 2021; 23: 1047-1064Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar This article focuses on two genes, TPMT encoding thiopurine methyltransferase and NUDT15 encoding nudix hydrolase 15, and is intended to provide guidance to clinical laboratorians and assay manufacturers who develop, validate, and/or offer clinical TPMT and NUDT15 genotyping assays. This document should be implemented together with other relevant clinical guidelines, including those published by the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Dutch Pharmacogenetics Working Group, the Canadian Pharmacogenomics Network for Drug Safety (for TPMT variants on cisplatin-induced hearing loss),7Lee J.W. Pussegoda K. Rassekh R.S. Monzon J.G. Liu G. Hwang S. Bhavsar A.P. Pritchard S. Ross C.J. Amstutz U. Carleton B.C. Hayden M.R. MacLeod S. Smith A. Brunham L. Aminkeng F. Shear N.H. Koren G. Ito S. Madadi P. Rieder M.J. Kim R. Maher M. Flockhart D. Clinical practice recommendations for the management and prevention of cisplatin-induced hearing loss using pharmacogenetic markers.Ther Drug Monit. 2016; 38: 423-431Crossref PubMed Scopus (33) Google Scholar and the French National Network of Pharmacogenetics, all of which focus primarily on the interpretation of PGx test results and therapeutic recommendations for specific drug–gene pairs (, last accessed January 20, 2022). The AMP PGx Working Group uses a two-tier strategy for selection criteria in recommending PGx variants for clinical testing.3Pratt V.M. Del Tredici A.L. Hachad H. Ji Y. Kalman L.V. Scott S.A. Weck K.E. Recommendations for clinical CYP2C19 genotyping allele selection: a report of the Association for Molecular Pathology.J Mol Diagn. 2018; 20: 269-276Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 4Pratt V.M. Cavallari L.H. Del Tredici A.L. Hachad H. Ji Y. Moyer A.M. Scott S.A. Whirl-Carrillo M. Weck K.E. Recommendations for clinical CYP2C9 genotyping allele selection: a joint recommendation of the Association for Molecular Pathology and College of American Pathologists.J Mol Diagn. 2019; 21: 746-755Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 5Pratt V.M. Cavallari L.H. Del Tredici A.L. Hachad H. Ji Y. Kalman L.V. Ly R.C. Moyer A.M. Scott S.A. Whirl-Carrillo M. Weck K.E. Recommendations for clinical warfarin genotyping allele selection: a report of the Association for Molecular Pathology and the College of American Pathologists.J Mol Diagn. 2020; 22: 847-859Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 6Pratt V.M. Cavallari L.H. Del Tredici A.L. Gaedigk A. Hachad H. Ji Y. Kalman L.V. Ly R.C. Moyer A.M. Scott S.A. van Schaik R.H.N. Whirl-Carrillo M. Weck K.E. Recommendations for clinical CYP2D6 genotyping allele selection: a joint consensus recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association.J Mol Diagn. 2021; 23: 1047-1064Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Briefly, Tier 1 recommended variant alleles are those that meet the following criteria: i) have a well-characterized effect on the function of the protein and/or gene expression, ii) have an appreciable minor allele frequency in a population/ethnicity group, iii) have publicly available reference materials, and iv) are technically feasible for clinical laboratories to interrogate using standard molecular testing methods. Tier 2 recommended variant alleles meet at least one but not all of the Tier 1 criteria; however, the Tier 2 alleles may be reclassified to Tier 1 in the future when additional information and/or reference material(s) becomes available. Thiopurine medications (6-mercaptopurine, 6-thioguanine, and azathioprine) commonly are prescribed as chemotherapeutic agents for the treatment of acute lymphoblastic leukemia, as immunosuppressant agents for the treatment of autoimmune disorders (eg, inflammatory bowel disease and rheumatoid arthritis), and to prevent organ transplant rejection.8Brunton L Parker K Lazo J Buxton I Blumenthal D Goodman & Gilman’s The Pharmacological Basis of Therapeutics. ed 11. McGraw-Hill, New York, NY2005Google Scholar However, they require extensive intracellular metabolism to generate active metabolites that are responsible for therapeutic efficacy. Importantly, two key detoxifying enzymes, thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15), act as negative modulators of both thiopurine activation and toxicity of thiopurine medications. The enzymatic activity of TPMT and NUDT15 is influenced directly by germline genetic variability in the TPMT and NUDT15 genes. Variant alleles are found in the general population at variable frequencies and contribute to interindividual differences in the pharmacologic and safety response profiles of thiopurine medications. As such, clinical PGx testing for genetic variants in TPMT and NUDT15 associated with diminished or absent enzymatic activity can identify individuals who are at increased risk of adverse drug toxicity with standard doses of thiopurine medications. The TPMT gene is located on chromosome 6p22.3, and was originally described as spanning 34 kb, and having 10 exons.9Wang L. Pelleymounter L. Weinshilboum R. Johnson J.A. Hebert J.M. Altman R.B. Klein T.E. Very important pharmacogene summary: thiopurine S-methyltransferase.Pharmacogenet Genomics. 2010; 20: 401-405Crossref PubMed Scopus (33) Google Scholar However, the MANE (Matched Annotation from NCBI and EMBL-EBI; , last accessed August 17, 2022) current NM_000367.5 transcript, used as the reference in this manuscript, has 9 exons (8 coding and 1 non-coding). Functional variants in the TPMT gene were found to contribute to the trimodal distribution of TPMT enzyme activity in red blood cells among individuals of European descent, with 89% having normal to high TPMT activity, 11% having low or intermediate activity, and approximately 0.3% of individuals having very low to absent TPMT activity.10Weinshilboum R.M. Sladek S.L. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity.Am J Hum Genet. 1980; 32: 651-662PubMed Google Scholar Subsequently, three alleles of the TPMT gene were identified to account for approximately 90% of reduced activity phenotypes among individuals of European descent: TPMT∗2, ∗3A, and ∗3C.11Schaeffeler E. Fischer C. Brockmeier D. Wernet D. Moerike K. Eichelbaum M. Zanger U.M. Schwab M. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants.Pharmacogenetics. 2004; 14: 407-417Crossref PubMed Scopus (384) Google Scholar Individuals who are heterozygous for one of these variants have approximately 50% enzyme activity and are predicted to be intermediate metabolizers, whereas individuals who are homozygous or compound heterozygous for these variants have very low to absent TPMT activity and are poor metabolizers. Importantly, both intermediate and poor TPMT metabolizers who receive a standard dose of thiopurine drugs are at increased risk of developing life-threatening myelosuppression. Nudix hydrolase 15 [or nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15); EC 3.6.1.9, also known as MutT homolog 2] is a member of the nudix hydrolase superfamily, which plays an important role in preventing transversion mutations in DNA. The NUDT15 enzyme preferentially hydrolyzes 6-thiodeoxyguanosine triphosphate and 6-thioguanosine triphosphate by conversion to 6-thio(deoxy)guanosine monophosphate, which prevents their incorporation into DNA and leads to reduced cytotoxic and immunosuppressant effects of thiopurine drugs.12Valerie N.C.K. Hagenkort A. Page B.D.G. Masuyer G. Rehling D. Carter M. Bevc L. Herr P. Homan E. Sheppard N.G. Stenmark P. Jemth A.S. Helleday T. NUDT15 hydrolyzes 6-thio-deoxyGTP to mediate the anticancer efficacy of 6-thioguanine.Cancer Res. 2016; 76: 5501-5511Crossref PubMed Scopus (71) Google Scholar The human NUDT15 gene is located on chromosome 13q14.2, spans 15 kb, and has three exons. A genetic variant, p.Arg139Cys, which is present in both NUDT15∗2 and ∗3, was first reported in 2014 to contribute to thiopurine toxicity by a genome-wide association study, and subsequently was replicated by several studies.13Yang S.K. Hong M. Baek J. Choi H. Zhao W. Jung Y. Haritunians T. Ye B.D. Kim K.J. Park S.H. Park S.K. Yang D.H. Dubinsky M. Lee I. McGovern D.P.B. Liu J. Song K. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia.Nat Genet. 2014; 46: 1017-1020Crossref PubMed Scopus (340) Google Scholar, 14Liu Y. Meng Y. Wang L. Liu Z. Li J. Dong W. Associations between the NUDT15 R139C polymorphism and susceptibility to thiopurine-induced leukopenia in Asians: a meta-analysis.Onco Targets Ther. 2018; 11: 8309-8317Crossref PubMed Scopus (19) Google Scholar, 15Yin D. Xia X. Zhang J. Zhang S. Liao F. Zhang G. Zhang Y. Hou Q. Yang X. Wang H. Ma Z. Wang H. Zhu Y. Zhang W. Wang Y. Liu B. Wang L. Xu H. Shu Y. Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose.Oncotarget. 2017; 8: 13575-13585Crossref PubMed Scopus (27) Google Scholar, 16Yang J.J. Landier W. Yang W. Liu C. Hageman L. Cheng C. Pei D. Chen Y. Crews K.R. Kornegay N. Wong F.L. Evans W.E. Pui C.H. Bhatia S. Relling M.V. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.J Clin Oncol. 2015; 33: 1235-1242Crossref PubMed Scopus (302) Google Scholar Multiple loss-of-function NUDT15 variants have been reported. The contribution of NUDT15 to thiopurine-related adverse effects such as leukopenia is as high as 22% among all ethnicities.16Yang J.J. Landier W. Yang W. Liu C. Hageman L. Cheng C. Pei D. Chen Y. Crews K.R. Kornegay N. Wong F.L. Evans W.E. Pui C.H. Bhatia S. Relling M.V. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.J Clin Oncol. 2015; 33: 1235-1242Crossref PubMed Scopus (302) Google Scholar The US Food & Drug Administration has included information about genetic variants in TPMT (for azathioprine, mercaptopurine, and thioguanine) and NUDT15 (for mercaptopurine and thioguanine) in the associated drug labels and the Pharmacogenetic Associations for which the Data Support Therapeutic Management Recommendations table (, last accessed January 20, 2022). In addition, dosing guidelines for thiopurines (azathioprine, mercaptopurine, and thioguanine) also have been published by CPIC17Relling M.V. Schwab M. Whirl-Carrillo M. Suarez-Kurtz G. Pui C.H. Stein C.M. Moyer A.M. Evans W.E. Klein T.E. Antillon-Klussmann F.G. Caudle K.E. Kato M. Yeoh A.E.J. Schmiegelow K. Yang J.J. Clinical Pharmacogenetics Implementation Consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update.Clin Pharmacol Ther. 2019; 105: 1095-1105Crossref PubMed Scopus (277) Google Scholar and the Dutch Pharmacogenetics Working Group (, last accessed January 20, 2022). Both CPIC and the Dutch Pharmacogenetics Working Group guidelines recommend specific dose reductions for individuals who have low or deficient enzyme activity (ie, TPMT or NUDT15 intermediate and poor metabolizers), predicted by TPMT and/or NUDT15 genotyping. Of note, TPMT also may be tested using an enzyme activity assay; however, there are no clinically available assays for NUDT15 enzyme activity. Selection of a molecular platform to use for testing PGx variants is based on many factors that include, but are not limited to, the technical feasibility of interrogating the genomic region of interest, cost, laboratory workflow, and test turnaround time required. Because both TPMT and NUDT15 genes reside on genomic regions that are amenable to testing using standard molecular techniques, PGx tests offered by clinical molecular genetics laboratories may use targeted genotyping or sequencing (Sanger sequencing or next-generation sequencing) approaches. However, it is up to the discretion of the specific laboratory to select the genotyping/sequencing method for clinical PGx test development and validation. Of note, most commonly used clinical molecular platforms (eg, genotyping, short-read next-generation sequencing) are unable to phase TPMT and NUDT15 variants. As such, assigning TPMT and NUDT15 diplotypes from raw genotyping or sequencing data are typically empiric or inferred. The AMP PGx Working Group comprises subject matter experts from the CPIC, Pharmacogenomics Knowledgebase (PharmGKB), College of American Pathologists (CAP), Dutch Pharmacogenetics Working Group, and the PGx clinical testing and research communities. TPMT and NUDT15 variant alleles were reviewed and classified into tiers on the basis of four criteria: i) functional characterization of the allele (ie, whether it is known to affect expression of the gene or function of the encoded protein); ii) an appreciable minor allele frequency (MAF) in a population and/or ethnic group [in this TPMT and NUDT15 recommendation document, the Working Group used a MAF of ≥0.1% in at least one subpopulation for Tier 1 alleles, and ≥0.01% for Tier 2 alleles based on currently available information from applicable resources (, and , last accessed January 20, 2022)]; iii) availability of reference materials (Table 1); and iv) technical feasibility for clinical laboratories to accurately interrogate the variant.Table 1Reference MaterialsAlleleCoriell†Novel haplotype; variants identifying TPMT∗8 and ∗33 were shown to be in cis by trio analysis using 1000 Genomes data (https://www.internationalgenome.org, last accessed January 20, 2022).DiplotypeAlleleCoriell†Novel haplotype; variants identifying TPMT∗8 and ∗33 were shown to be in cis by trio analysis using 1000 Genomes data (https://www.internationalgenome.org, last accessed January 20, 2022).DiplotypeTPMT∗2HG00133(∗1/∗2)NUDT15∗2HG00599(∗2/∗32)HG01083(∗1/∗2)NA19079(∗2/∗5)TPMT∗3ANA12753∗1/∗3ANUDT15∗3NA18992∗1/∗3NA15245∗1/∗3AHG00524(∗3/∗3)TPMT∗3BNone-NA18564∗1/∗3TPMT∗3CHG00589∗1/∗3CNUDT15∗4HG01359∗1/∗4NA18855∗1/∗3CHG01465(∗1/∗4)TPMT∗4None-NUDT15∗5HG00437∗1/∗5TPMT∗5None-NA23093∗1/∗5TPMT∗6NA18603(∗1/∗6)NUDT15∗6HG00277(∗1/∗6)TPMT∗7None-NA07000(∗1/∗6)TPMT∗8NA19176∗1/∗8NA07029(∗1/∗6)NA23275∗1/∗8NUDT15∗7None-TPMT∗9None-NUDT15∗8None-TPMT∗10None-NUDT15∗9HG01086(∗2/∗9)TPMT∗11None-NUDT15∗10None-TPMT∗12NA12751(∗1/∗12)NUDT15∗11None-TPMT∗13None-NUDT15∗12None-TPMT∗14None-NUDT15∗13None-TPMT∗15None-NUDT15∗14None-TPMT∗16HG00276(∗1/∗16)NUDT15∗16None-TPMT∗16HG00304(∗3A/∗16)NUDT15∗15None-TPMT∗17None-NUDT15∗17None-TPMT∗18None-NUDT15∗18None-TPMT∗19None-NUDT15∗19None-TPMT∗20None-NUDT15∗20None-TPMT∗21NA12044(∗1/∗21)TPMT∗22None-TPMT∗23None-TPMT∗24HG02496(∗1/∗24)TPMT∗25None-TPMT∗26None-TPMT∗27None-TPMT∗28None-TPMT∗29None-TPMT∗30None-TPMT∗31None-TPMT∗32NA10855(∗1/∗32)TPMT∗33NA19026(∗8/∗33)‡The ∗8 and ∗33 variants were not phased in this sample.TPMT∗34None-TPMT∗35None-TPMT∗36None-TPMT∗37None-TPMT∗38None-TPMT∗39None-TPMT∗40HG01474(∗1/∗40)TPMT∗41None-TPMT∗42None-TPMT∗43None-TPMT∗44None-TPMT∗46HG03521(∗1/∗46)‡The ∗8 and ∗33 variants were not phased in this sample.Diplotypes in parentheses are included in Pratt et al.18Pratt VM Wang WY Boone EC Broeckel U Cody N Edelmann L Gaedigk A Lynnes TC Medeiros EB Moyer AM Mitchell MW Scott SA Starostik P Turner A Kalman LV Characterization of reference materials for TPMT and NUDT15: A GeT-RM collaborative project.J Mol Diagn. 2022; 24: 1079-1088Abstract Full Text Full Text PDF Google Scholar† Novel haplotype; variants identifying TPMT∗8 and ∗33 were shown to be in cis by trio analysis using 1000 Genomes data (, last accessed January 20, 2022).‡ The ∗8 and ∗33 variants were not phased in this sample. Open table in a new tab Diplotypes in parentheses are included in Pratt et al.18Pratt VM Wang WY Boone EC Broeckel U Cody N Edelmann L Gaedigk A Lynnes TC Medeiros EB Moyer AM Mitchell MW Scott SA Starostik P Turner A Kalman LV Characterization of reference materials for TPMT and NUDT15: A GeT-RM collaborative project.J Mol Diagn. 2022; 24: 1079-1088Abstract Full Text Full Text PDF Google Scholar These criteria received equal weight during the AMP PGx Working Group deliberations. In addition, commercially available genotyping platforms (Supplemental Table S1) were reviewed for assessing the ability of laboratories to implement the Working Group recommendations; however, these data were not used as a determinant of tier assignment. The AMP PGx Working Group used MAF and functional information from the CPIC, PharmGKB, and scientific literature. Given that the CPIC clinical dosing guideline development process includes curating allele frequencies and function assignments, the PGx Working Group incorporated CPIC's curated information. In some populations, including those of European, Latino, and Near Eastern descent, the most common variant TPMT allele is ∗3A, which is a haplotype with the ∗3B and ∗3C alleles in cis. Single-variant frequencies can be found in databases such as the Genome Aggregation Database (, last accessed January 20, 2022) and the International Genome Sample Resource (or 1000 Genomes, , last accessed January 20, 2022), but these resources do not report frequencies of allele haplotypes such as TPMT∗3A. The CPIC relies on studies from peer-reviewed published literature for these allele frequencies. However, there are caveats with obtaining frequencies from published studies. For example, most studies test for a limited number of alleles, and some alleles rarely are assayed or reported in the literature. In addition, most studies default allele assignment to TPMT∗1 if none of the interrogated variants are detected. As a result, allele frequencies can be underestimated, overestimated, or simply not reported. The CPIC allele clinical function assignment is based on literature reviews of allele function by guideline (, last accessed January 20, 2022), which may not be consistent with the CPIC-defined biochemical function of the allele. TPMT nomenclature is maintained at Linköping University in Linköping, Sweden (, last accessed January 20, 2022). The website currently catalogs 43 variant TPMT star (∗) alleles, TPMT∗2-∗44. NUDT15 nomenclature was introduced by the Pharmacogene Variation Consortium (, last accessed January 20, 202).19Yang J.J. Whirl-Carrillo M. Scott S.A. Turner A.J. Schwab M. Tanaka Y. Suarez-Kurtz G. Schaeffeler E. Klein T.E. Miller N.A. Gaedigk A. Pharmacogene Variation Consortium gene introduction: NUDT15.Clin Pharmacol Ther. 2019; 105: 1091-1094Crossref PubMed Scopus (29) Google Scholar The Pharmacogene Variation Consortium lists 20 variant NUDT15 star (∗) alleles, NUDT15∗2-∗20. All NUDT15 star alleles are defined by a single variant with the exception of NUDT15∗2, which is defined by two variants in cis that also can occur separately. Although the Pharmacogene Variation Consortium currently lists 20 NUDT15 alleles, the CPIC last evaluated NUDT15 alleles up to ∗9 for the 2018 thiopurine guideline update. To determine the frequency of clinical laboratories that currently test for TPMT and/or NUDT15 variants, aggregate data from the CAP proficiency testing (PT) program was obtained from the 2021 PGX-A mailing.20CAP Biochemical and Molecular Genetics CommitteePGX-A, 2021 Proficiency Testing Survey. College of American Pathologists, Northfield, IL2021Google Scholar The CAP PGx PT program includes both US-based and international participants.6Pratt V.M. Cavallari L.H. Del Tredici A.L. Gaedigk A. Hachad H. Ji Y. Kalman L.V. Ly R.C. Moyer A.M. Scott S.A. van Schaik R.H.N. Whirl-Carrillo M. Weck K.E. Recommendations for clinical CYP2D6 genotyping allele selection: a joint consensus recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association.J Mol Diagn. 2021; 23: 1047-1064Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar External assessment programs in Europe such as the European Molecular Genetics Quality Network and the Reference Institute for Bioanalytics also were reviewed. TPMT and NUDT15 star (∗) alleles recommended for inclusion in Tier 1 include TPMT∗2, ∗3A, ∗3B, ∗3C, and NUDT15∗3 (Table 2). For Human Genome Variation Society nomenclature throughout, see and (last accessed January 20, 2022); allele frequency by population information is from (last accessed January 20, 2022) unless otherwise specified.Table 2Tier 1 TPMT and NUDT15 Variant AllelesAlleleAllele functional status†Citations for assignment of function can be found at https://www.pharmvar.org; HGVS nomenclature https://www.ncbi.nlm.nih.gov/snp; and http://www.ncbi.nlm.nih.gov/clinvar (last accessed January 20, 2022).Core variant(s)‡Core variant(s) can be found at https://www.pharmvar.org (last accessed January 20, 2022).RefSeqGene LRG nomenclatureHGVS genomic nomenclature (GRCh38)HGVS cDNA nomenclatureHGVS protein nomenclatureReference material availableMultiethnic allele frequency, %TPMT∗2No functionrs1800462NG_012137.3: g.16420G>CNC_000006.12: g.18143724C>GNM_000367.5: c.238G>CNP_000358.1: p.Ala80ProYes§Pratt et al.180–0.7TPMT∗3ANo functionrs1800460, rs1142345NG_012137.3: g.21147G>A, NG_012137.3: g.29457A>GNC_000006.12: g.18138997C>T, NC_000006.12: g.18130687T>CNM_000367.5: c.460G>A, NM_000367.5: c.719A>GNP_000358.1: p.Ala154Thr, NP_000358.1: p.Tyr240CysYes0.03–4.2TPMT∗3BNo functionrs1800460NG_012137.3: g.21147G>ANC_000006.12: g.18138997C>TNM_000367.5: c.460G>ANP_000358.1: p.Ala154ThrYes (∗3A)0–0.5TPMT∗3CNo functionrs1142345NG_012137.3: g.29457A>GNC_000006.12: g.18130687T>CNM_000367.5: c.719A>GNP_000358.1: p.Tyr240CysYes0.6–5.3NUDT15∗3No functionrs116855232NG_047021.1: g.13153C>TNC_000013.11: g.48045719C>TNM_018283.4: c.415C>TNP_060753.1: p.Arg139CysYes§Pratt et al.180–6.8HGVS, Human Genome Variation Society; LRG, Locus Reference Genomic.† Citations for assignment of function can be found at ; HGVS nomenclature ; and (last accessed January 20, 2022).‡ Core variant(s) can be found at (last accessed January 20, 2022).§ Pratt et al.18Pratt VM Wang WY Boone EC Broeckel U Cody N Edelmann L Gaedigk A Lynnes TC Medeiros EB Moyer AM Mitchell MW Scott SA Starostik P Turner A Kalman LV Characterization of reference materials for TPMT and NUDT15: A GeT-RM collaborative project.J Mol Diagn. 2022; 24: 1079-1088Abstract Full Text Full Text PDF Google Scholar Open table in a new tab HGVS, Human Genome Variation Society; LRG, Locus Reference Genomic. The no-function TPMT∗2 allele is characterized by a missense variant in exon 4 (NM_000367.5:c.238G>C, p.Ala80Pro, rs18004622).21Krynetski E.Y. Schuetz J.D. Galpin A.J. Pui C.H. Relling M.V. Evans W.E. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase.Proc Natl Acad Sci U S A. 1995; 92: 949-953Crossref PubMed Scopus (299) Google Scholar, 22Salavaggione O.E. Wang L. Wiepert M. Yee V.C. Weinshilboum R.M. Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics.Pharmacogenet Genomics. 2005; 15: 801-815Crossref PubMed Scopus (119) Google Scholar, 23Tai H.L. Krynetski E.Y. Schuetz E.G. Yanishevski Y. Evans W.E. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT∗3A, TPMT∗2): mechanisms for the genetic polymorphism of TPMT activity.Proc Natl Acad Sci U S A. 1997; 94: 6444-6449Crossref PubMed Scopus (239) Google Scholar, 24Ujiie S. Sasaki T. Mizugaki M. Ishikawa M. Hiratsuka M. Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT∗2 - ∗24).Pharmacogenet Genomics. 2008; 18: 887-893Crossref PubMed Scopus (72) Google Scholar, 25Tai H.L. Krynetski E.Y. Yat" @default.
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• W4289525431 cites W1534517380 @default.
• W4289525431 cites W1574225715 @default.
• W4289525431 cites W1996409190 @default.
• W4289525431 cites W1998066609 @default.
• W4289525431 cites W2016756549 @default.
• W4289525431 cites W2027950584 @default.
• W4289525431 cites W2030222200 @default.
• W4289525431 cites W2033674020 @default.
• W4289525431 cites W2035126894 @default.
• W4289525431 cites W2060310903 @default.
• W4289525431 cites W2063213712 @default.
• W4289525431 cites W2064928200 @default.
• W4289525431 cites W2076472107 @default.
• W4289525431 cites W2081749017 @default.
• W4289525431 cites W2084271415 @default.
• W4289525431 cites W2085038188 @default.
• W4289525431 cites W2095087319 @default.
• W4289525431 cites W2109000403 @default.
• W4289525431 cites W2178874084 @default.
• W4289525431 cites W2275947820 @default.
• W4289525431 cites W2309021002 @default.
• W4289525431 cites W2335023411 @default.
• W4289525431 cites W2507559166 @default.
• W4289525431 cites W2512386861 @default.
• W4289525431 cites W2556561592 @default.
• W4289525431 cites W2575210492 @default.
• W4289525431 cites W2731117318 @default.
• W4289525431 cites W2741658794 @default.
• W4289525431 cites W2789160819 @default.
• W4289525431 cites W2900673338 @default.
• W4289525431 cites W2900951625 @default.
• W4289525431 cites W2903466396 @default.
• W4289525431 cites W2915002766 @default.
• W4289525431 cites W2937906550 @default.
• W4289525431 cites W2944063617 @default.
• W4289525431 cites W3023063284 @default.
• W4289525431 cites W3088394431 @default.
• W4289525431 cites W3094646577 @default.
• W4289525431 cites W3172385553 @default.
• W4289525431 cites W4289526948 @default.
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