The TPMT NM_000367.5:c.719A>G (NP_000358.1:p.(Tyr240Cys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV59428256, n = 9 times). Experimental evidence: TPMT*3C/A719G carriers showed intermediate activity, with median 7.8 U/ml in African-Americans and 7.0 U/ml in the Caucasian carrier. Based on available guidelines, this variant is considered to be Benign.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.TPMT encodes an enzyme that helps break down thiopurine medicines, including 6-mercaptopurine. Differences in TPMT activity can affect how strongly a person responds to these drugs and can increase the risk of treatment-related toxicity; reduced activity is known as thiopurine S-methyltransferase deficiency. TPMT is not currently established as an oncogene or tumor suppressor and is only infrequently altered in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: TPMT*3C/A719G carriers showed intermediate activity, with median 7.8 U/ml in African-Americans and 7.0 U/ml in the Caucasian carrier.
Met at supporting: REVEL 0.703 exceeds the generic PP3 supporting threshold of >=0.644 for missense variants.
Met: gnomAD v4.1 grpmax FAF is 5.374767%, exceeding the 5% BA1 threshold with 4,132 observed alleles in the contributing population.
Benign: BA1 stand-alone benign is met by the variant's population frequency; PS3 and PP3 supporting evidence does not satisfy a pathogenic combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 68,904 / 1,609,224 alleles. Recorded AF 0.0428182. Recorded homozygote count 1714.
This variant is present in gnomAD v2.1 (AF= 0.0371849; MAF= 3.71849%, 10506/282534 alleles, homozygotes = 268) and has highest observed frequency in the African/African American population (AF= 0.0552873; MAF= 5.52873%, 1374/24852 alleles, homozygotes = 42); grpmax FAF= 0.0525048.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.703. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Likely benign · 1 other. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TPMT, a thiopurine S-methyltransferase, is infrequently altered in cancer.
This variant has previously been reported in somatic cancers (COSMIC; COSV59428256, n = 9 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP covers TPMT in this case; generic ACMG/AMP definitions govern.
The available evidence is pharmacogenetic and population-based rather than a qualifying disease-specific phenotype, alternate-molecular-basis case, or expert-panel assertion.
ClinVar expert-panel submissions are absent, so laboratory Likely benign labels do not trigger BP6 and no pathogenic expert-panel label triggers PP5.
The variant is missense, so PP3 and BP4 are adjudicated exclusively through REVEL.
REVEL 0.703 meets PP3 supporting (>=0.644) and does not meet BP4 supporting (<=0.29).
BA1 is met as stand-alone benign evidence from the gnomAD filtering allele frequency; the allele is common and the available ClinVar consensus is Likely benign.
BS1 is not assessed because no defined Mendelian disorder model or maximum-credible-frequency inputs are available for this pharmacogenomic allele.
BS2 is not assessed because population homozygote counts do not establish phenotype-verified healthy adults or early-age full penetrance for this exposure-dependent pharmacogenetic trait.
PM2 is not met because the variant is common in gnomAD.
No criteria match.
PS3 is met at supporting strength. PMID:9931346 directly studied the A719G allele corresponding to NM_000367.5:c.719A>G (TPMT*3C) in a cohort of 248 African-Americans and 282 Caucasian Americans. The study used PCR-based mutation detection, including restriction-enzyme analysis for A719G, and measured TPMT enzymatic activity in packed red blood cells. Among African-American TPMT*3C heterozygotes, median activity was 7.8 U/ml, compared with 7.0 U/ml in the Caucasian TPMT*3C heterozygote, and the variant was found among individuals with intermediate TPMT activity. This is biologically relevant, variant-specific functional evidence supporting reduced TPMT activity, but the available extraction does not establish validation, reproducibility, or robustness in a clinical diagnostic laboratory setting; therefore strong PS3 is not justified.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
This is a missense variant, so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. The REVEL score is 0.703, which meets the supplied PP3 supporting threshold of >= 0.644. The threshold is the ClinGen SVI REVEL calibration from Pejaver et al. 2022 (PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established, and no splice prediction is available or applicable to this missense path.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BA1 is met. The default all-comers gnomAD v4.1 result is used because no VCEP specifies a non-cancer or exome-only source. The filtering frequency is the grpmax FAF, 0.05374767 (5.374767%), above the generic BA1 threshold of 0.05. The grpmax population is African/African American, with 4,132 observed alleles, exceeding the required 2,000-allele minimum; the point-estimate popmax AF is not used. The gnomAD v2.1 result is concordant (grpmax FAF 0.0525048). The variant is a well-established common TPMT*3C pharmacogenetic allele and ClinVar reports a Likely benign consensus without an expert-panel pathogenic consensus, so the high frequency does not create the pathogenic-consensus conflict that would preclude a stand-alone BA1 call.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
The variant is TPMT c.719A>G, p.Tyr240Cys (Y240C). The cited ClinVar record classifies this exact variant as likely benign with no expert-panel submission, and the reviewed variant-specific paper identifies it as TPMT*3C/A719G in population cohorts rather than documenting an independently established pathogenic variant with the same amino-acid change. Therefore, the required prior pathogenic same-amino-acid observation for PS1 is not established.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No qualifying case-control enrichment study was identified for NM_000367.5:c.719A>G (TPMT*3C; p.Tyr240Cys). The PS4-indexed literature was checked: PMID:15819814 is a single patient with TPMT*3A/*3C and does not report this exact variant or controls; PMID:16476125 is a population allele study listed in the literature packet but no case-control affected-versus-unaffected comparison is available in the supplied evidence; PMID:9931346 reports TPMT*3C frequencies among intermediate-activity subjects and ethnic population samples, not affected-disease cases versus controls. Therefore no case/control counts support calculation of an OR and 95% CI, and the PS4 threshold is not met. The governing numeric direction is ">5.0"; because no OR or RR is available, no substituted inequality can be evaluated.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
TPMT p.Tyr240Cys is present at substantial population frequency: gnomAD v4.1 AF 0.0428182, with 68,904 of 1,609,224 alleles and 1,714 homozygotes; the African/African American AF is 0.0551522. This common variation contradicts the PM1 requirement for a critical domain or hotspot without benign variation. No VCEP domain table or approved TPMT hotspot route is present, and Cancer Hotspots returned no statistically significant hotspot.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met. The default all-comers population sources are used because no VCEP specifies a non-cancer or exome-only source. The variant is common in gnomAD v4.1 (total AF=0.0428181533; 68,904/1,609,224 alleles; 1,714 homozygotes) and gnomAD v2.1 (total AF=0.0371849052; 10,506/282,534 alleles; 268 homozygotes), far above the generic PM2 supporting threshold of 0.0001. The gnomAD v2.1 non-cancer exome-only AF is also common at 0.0364689, but it is not needed to reject PM2.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
No exact-variant ClinVar expert-panel or other qualifying reputable-source Pathogenic/Likely pathogenic classification was identified. ClinVar reports Likely benign submissions from clinical laboratories and no expert-panel submissions; ordinary laboratory submissions and aggregate labels do not satisfy the required PP5 source condition. The literature trail contains no exact-variant reputable-source pathogenic assertion that is unavailable for independent evaluation.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
This is a missense variant, so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. The REVEL score is 0.703, which is above the supplied BP4 supporting cutoff of <= 0.29, so it does not support no impact. The result is therefore not BP4; the unavailable SpliceAI result and uncalibrated BayesDel score cannot substitute for or add to the applicable REVEL path.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
No exact-variant ClinVar expert-panel or other qualifying reputable-source benign/Likely benign assertion was identified as evidence unavailable for independent evaluation. ClinVar shows Likely benign laboratory submissions but zero expert-panel submissions; ordinary laboratory submissions and aggregate ClinVar labels are excluded from BP6 under the specified rule.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No proband-level de novo observation is documented for NM_000367.5:c.719A>G (TPMT p.Tyr240Cys). The available evidence contains no affected-patient phenotype assessment, no parental genotypes, and no confirmation of both maternity and paternity; therefore PS2 cannot be applied.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PM3 cannot be assessed because the available evidence does not document an affected proband carrying NM_000367.5:c.719A>G in trans with a pathogenic variant, and no parental or offspring testing establishes phase. The variant was reported as TPMT*3C in a population/activity cohort, but the cited cohort does not provide a recessive affected-proband trans observation for this variant.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The available PM5 candidate file contains no same-residue comparator variants and explicitly states that classic PM5 semantics could not be confirmed safely. The available literature extraction documents the observed c.719A>G variant but does not establish a different pathogenic missense change at Tyr240. A verified pathogenic comparator at residue 240 is therefore still required.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No assumed-de novo observation is documented for NM_000367.5:c.719A>G (TPMT p.Tyr240Cys). The available evidence contains no affected-patient phenotype assessment or parental testing information, so PM6 cannot be applied.
Assumed de novo, but without confirmation of paternity and maternity.
No affected relatives, informative meioses, pedigree, parental testing, or variant-specific co-segregation analysis is documented for NM_000367.5:c.719A>G (TPMT p.Tyr240Cys). The available TPMT literature describes population allele frequencies and pharmacogenetic activity but does not establish co-segregation with disease in multiple affected family members.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The available evidence does not establish both PP2 gene-level prerequisites: a low rate of benign missense variation and missense variants as a common disease mechanism for TPMT. The high population frequency of this missense variant argues against treating TPMT missense variation as uniformly rare, but it does not quantify the gene-wide benign missense rate or establish the disease mechanism required by PP2.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The supplied case and literature do not establish a patient phenotype or family history that is highly specific for a disease with a single genetic etiology. The available TPMT papers describe pharmacogenetic enzyme activity, drug toxicity, or population allele frequencies rather than a disease-specific phenotype for this exact variant. The evidence is therefore insufficient to assess PP4.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS1 is not assessed. The filtering allele frequency is far above the supplied generic 0.01 default (0.05374767 in gnomAD v4.1 and 0.05250484 in gnomAD v2.1), but BS1 requires that the allele frequency be greater than expected for a defined disorder. This case concerns a TPMT pharmacogenomic allele and supplies no Mendelian disease prevalence, penetrance, allelic heterogeneity, or maximum-credible-frequency inputs with which to determine whether the observed ancestry-enriched frequency is excessive for a disorder. Whiffin et al. 2017 (PMID:28518168) is the relevant maximum-credible-frequency framework, but its inputs are unavailable here.
Allele frequency is greater than expected for disorder.
BS2 is not assessed. gnomAD reports many homozygotes (268 in v2.1 and 1,714 in v4.1), but gnomAD is not a phenotype-verified healthy-adult cohort for TPMT deficiency, and the available evidence does not establish that full penetrance of a disease phenotype is expected at an early age. TPMT*3C is a common pharmacogenetic allele whose clinical effect is exposure-dependent, so homozygote counts alone cannot satisfy the BS2 healthy-adult criterion.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No available study provides well-established functional evidence showing that NM_000367.5:c.719A>G (p.Tyr240Cys; TPMT*3C) has no damaging effect on TPMT protein function or splicing. The variant-specific study identified intermediate TPMT activity rather than a normal-function result, and the other reviewed sources did not provide a variant-specific benign functional assay.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected relative who lacks NM_000367.5:c.719A>G (TPMT p.Tyr240Cys), no genotype-phenotype discordance, no auditable pedigree, and no variant-specific non-segregation analysis is documented. The available TPMT literature does not establish lack of segregation in affected family members; therefore BS4 cannot be applied.
Lack of segregation in affected members of a family.
The evidence supports TPMT loss-of-function pharmacogenetic effects and describes common inactivating alleles, but it does not establish that disease-causing variants in TPMT are primarily truncating rather than missense or otherwise define the disease variant spectrum required for BP1. Therefore BP1 cannot be assigned from the available evidence.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed because the available evidence does not document NM_000367.5:c.719A>G in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant. The available TPMT*3C cohort reports do not provide phase information with another pathogenic variant.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
No case evidence supplied for this exact variant demonstrates an alternate molecular basis for the patient's disease. The available reports concern TPMT pharmacogenetic activity or drug toxicity and do not establish an alternate molecular etiology for a disease case. The evidence is insufficient to assess BP5.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000367.5:c.719A>G in TPMT is a missense substitution predicted to produce NP_000358.1:p.(Tyr240Cys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for TPMT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000367.5:c.719A>G in TPMT is a missense substitution predicted to produce NP_000358.1:p.(Tyr240Cys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for TPMT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000367.5:c.719A>G in TPMT is a missense substitution predicted to produce NP_000358.1:p.(Tyr240Cys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for TPMT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000367.5:c.719A>G in TPMT is a missense substitution predicted to produce NP_000358.1:p.(Tyr240Cys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for TPMT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in TPMT, mapped onto the exon structure of NM_000367.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American4132 / 74,920 | 0.055143 hom |
| Admixed American2941 / 60,014 | 0.04983 hom |
| European (non-Finnish)55001 / 1,176,868 | 0.0471366 hom |
| Remaining individuals2245 / 62,266 | 0.03644 hom |
| European (Finnish)1924 / 64,020 | 0.0337 hom |
| South Asian1532 / 90,942 | 0.01731 hom |
| Amish15 / 910 | 0.0161 hom |
| Ashkenazi Jewish476 / 29,570 | 0.0166 hom |
| East Asian585 / 44,810 | 0.0133 hom |
| Middle Eastern53 / 4,904 | 0.011 |
| African/African American1374 / 24,852 | 0.05542 hom |
| Admixed American1682 / 35,416 | 0.04747 hom |
| European (non-Finnish)5493 / 129,006 | 0.043143 hom |
| Remaining individuals249 / 7,208 | 0.03510 hom |
| European (Finnish)748 / 25,120 | 0.0312 hom |
| South Asian545 / 30,612 | 0.01811 hom |
| East Asian282 / 19,954 | 0.0142 hom |
| Ashkenazi Jewish133 / 10,366 | 0.0131 hom |
This variant is present in gnomAD v4.1 (AF= 0.0428182; MAF= 4.28182%, 68904/1609224 alleles, homozygotes = 1714) and has highest observed frequency in the African/African American population (AF= 0.0551522; MAF= 5.51522%, 4132/74920 alleles, homozygotes = 143); grpmax FAF= 0.0537477.
This variant is present in gnomAD v2.1 (AF= 0.0371849; MAF= 3.71849%, 10506/282534 alleles, homozygotes = 268) and has highest observed frequency in the African/African American population (AF= 0.0552873; MAF= 5.52873%, 1374/24852 alleles, homozygotes = 42); grpmax FAF= 0.0525048.
Not available in gnomAD-Canada v1.0.
This is a missense variant, so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. The REVEL score is 0.703, which meets the supplied PP3 supporting threshold of >= 0.644. The threshold is the ClinGen SVI REVEL calibration from Pejaver et al. 2022 (PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established, and no splice prediction is available or applicable to this missense path.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
This is a missense variant, so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. The REVEL score is 0.703, which is above the supplied BP4 supporting cutoff of <= 0.29, so it does not support no impact. The result is therefore not BP4; the unavailable SpliceAI result and uncalibrated BayesDel score cannot substitute for or add to the applicable REVEL path.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000367.5:c.719A>G in TPMT is a missense substitution predicted to produce NP_000358.1:p.(Tyr240Cys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for TPMT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
REVEL score = 0.703. BayesDel score = 0.244235.
9 paper records listed. 1 cited in the classification.
TPMT*3C was the most prevalent mutant allele found in African-Americans (12 of 23 subjects, 52.2%), whereas it was found significantly less frequently in Caucasians (one of 21 subjects, 4.8%, P < 0.001).
Location Results, paragraph beginning “Table 1 summarizes”; Table 1; Table 2; Discussion
Context TPMT genotyping in 248 African-Americans and comparison with 282 Caucasian Americans; intermediate-activity individuals underwent PCR-based mutation detection including restriction-enzyme analysis for A719G, and TPMT activity was measured in packed red blood cells.
The subject was found to be a TPMT*3A/*3C compound homozygote.
Case description, genotype and discussion paragraphs
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.0428182; MAF= 4.28182%, 68904/1609224 alleles, homozygotes = 1714) and has highest observed frequency in the African/African American population (AF= 0.0551522; MAF= 5.51522%, 4132/74920 alleles, homozygotes = 143); grpmax FAF= 0.0537477.
This variant is present in gnomAD v2.1 (AF= 0.0371849; MAF= 3.71849%, 10506/282534 alleles, homozygotes = 268) and has highest observed frequency in the African/African American population (AF= 0.0552873; MAF= 5.52873%, 1374/24852 alleles, homozygotes = 42); grpmax FAF= 0.0525048.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as other (1 clinical laboratory). (ClinVarID = 12725)
REVEL score = 0.703. BayesDel score = 0.244235.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TPMT, a thiopurine S-methyltransferase, is infrequently altered in cancer.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59428256, n = 9 times).
This variant does not lie in a statistically significant hotspot.