BRCA2 c.10202C>T, p.Thr3401Met
NM_000059.4:c.10202C>T
COSMIC ID: COSM3417537
Variant of Uncertain Significance (VUS)
BRCA2 p.T3401M is a missense variant absent from population databases (PM2_Supporting) and lies outside known functional domains with no predicted splicing impact (BP1_Strong). No additional pathogenic or benign evidence is available, leading to a final classification of Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP1
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.10202C>T
Protein Change
T3401M
Location
Exon 27
(Exon 27 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 3401 in gene BRCA2
Alternate Identifiers
COSM3417537
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.10202C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
4 publications
Uncertain Significance (VUS)
Based on 16 submitter reviews in ClinVar
Submitter Breakdown
10 VUS
5 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
The p.T3401M variant (also known as c.10202C>T), located in coding exon 26 of the BRCA2 gene, results from a C to T substitution at nucleotide position 10202. The threonine at codon 3401 is replaced by methionine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Górski B et al. Am. J. Hum. Genet. 2000 Jun;66:1963-8; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). In a study of 2984 breast cancer cases, 4376 prostate cancer cases, and 7545 controls this alteration was observed with an allele frequency of 0.000384 in Latinos (Haiman CA et al. PLoS Genet., 2013 Mar;9:e1003419). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
The BRCA2 c.10202C>T (p.Thr3401Met) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 35402282 (2022), 34290354 (2021), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/), 25682074 (2015), 28569218 (2017), 20223018 (2006)), ovarian cancer (PMID: 24504028 (2014), 26843898 (2016)), colon cancer (PMID: 10788334 (2000)), and bile duct cancer (PMID: 32885271 (2021)). This variant has also been identified in reportedly unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Variant summary: BRCA2 c.10202C>T (p.Thr3401Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 305166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10202C>T has been reported in the literature in individuals affected with breast and ovarian cancers (e.g. (Gorski_2000, Gorski_2006, Cunningham_2014, Haiman_2013, Wong-Brown_2015, Melloni_2017 Abdel-Razeq_2021, Guo_2020) as well as prostate cancer(Fei_2021) and colorectal cancer (Deihimi_2017), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34290354, 24504028, 28591715, 34709755, 20223018, 10788334, 31837001, 23555315, 28569218, 25682074). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=7) or benign (n=1)/likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (10 clinical laboratories) and as Benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 3401 in gene BRCA2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows it is a missense change (T3401M), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PS1 is: "Strong: Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1))". The evidence for this variant shows no previously established pathogenic variant at the same amino acid. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows no functional characterization. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control studies; p-value ≤0.05 and OR ≥4)". The evidence for this variant shows no case-control data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation". The evidence for this variant shows it lies outside the BRCA2 PALB2‐binding (aa 10–40) and DNA‐binding (aa 2481–3186) domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PM2 is: "Supporting: Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer)". The evidence for this variant shows a MAF of 0% and absence from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PM3 is: "Supporting/Moderate/Strong: Apply for patient with phenotype consistent with BRCA2-related Fanconi anemia and co-occurring variants in the same gene". The evidence for this variant shows no Fanconi anemia phenotype or trans co-occurrence. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants". The evidence for this variant shows no insertion/deletion or stop‐loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before". The evidence for this variant shows no other pathogenic missense at residue 3401. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PP1 is: "Supporting/Moderate/Strong: Co-segregation with disease in multiple affected family members measured by a quantitative method". The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant in BRCA2 is insufficient to meet that context. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PP3 is: "Supporting: Apply for missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.30 or predicted splicing impact (SpliceAI ≥0.2)". The evidence for this variant shows it is outside known functional domains and SpliceAI=0.02. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for PP4 is: "Supporting/Moderate/Strong: Use only for multifactorial likelihood clinical data (LR ≥2.08) in breast cancer". The evidence for this variant shows no multifactorial data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic". The evidence for this variant shows conflicting ClinVar assertions. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BA1 is: "Stand Alone: Filter allele frequency (FAF) above 0.1% in gnomAD". The evidence for this variant shows absent frequency. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BS1 is: "Strong: Filter allele frequency (FAF) above 0.01% in gnomAD". The evidence for this variant shows absent frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BS2 is: "Supporting/Moderate/Strong: Applied in absence of Fanconi anemia features in healthy individuals". The evidence for this variant shows no healthy adult observation data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BS3 is: "Strong: Well-established functional studies show no damaging effect". The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BS4 is: "Supporting/Moderate/Strong: Lack of segregation in affected family members". The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BP1 is: "Strong: Apply BP1_Strong for missense variants outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)". The evidence for this variant shows T3401M lies outside BRCA2 functional domains and SpliceAI=0.02. Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis with a pathogenic variant for a dominant disorder or in trans with a pathogenic variant for a recessive disorder". The evidence for this variant shows no co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function". The evidence for this variant shows no in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BP4 is: "Supporting: Missense variants inside a clinically important domain with BayesDel no-AF ≤0.18 AND SpliceAI ≤0.1". The evidence for this variant shows it is outside functional domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BP5 is: "Supporting/Moderate/Strong: Cases with pathogenic variants in two different known breast–ovarian cancer risk genes have no specific phenotype". The evidence for this variant shows no such co-observation. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign". The evidence for this variant shows conflicting ClinVar assertions. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP BRCA2 guidelines, the rule for BP7 is: "Supporting: Silent or intronic variants outside splice sites if BP4 met". The evidence for this variant shows a missense change. Therefore, this criterion is not applied.