BRCA2 c.9242T>C, p.Val3081Ala
NM_000059.4:c.9242T>C
Variant of Uncertain Significance (VUS)
A well-established functional study shows no damaging effect (BS3 Strong) and no evidence supports pathogenicity. Under VCEP rules, this single strong benign criterion yields a Likely Benign classification.
ACMG/AMP Criteria Applied
BS3
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.9242T>C
Protein Change
V3081A
Location
Exon 24
(Exon 24 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 3081 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.9242T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0012%
Rare
Highest in Population
South Asian
0.0033%
Rare
Global: 0.0012%
South Asian: 0.0033%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250360Alt: 3Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0012%, 3/250360 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.0033%, 1/30348 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Uncertain Significance (VUS)
Based on 15 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
9 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Variant summary: BRCA2 c.9242T>C (p.Val3081Ala) results in a non-conservative amino acid change located in the OB3 fold (IPR015188) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 347936 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9242T>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and related tumor phenotypes, it was also found in several healthy controls (Grant_2015, Shimelis_2017, Zuntini_2018, Al Hannan_2019). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8364G>A, p.Trp2788X; in UMD), providing supporting evidence for a benign role. An in vitro functional study reported that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (Guidugli_2018, Hart_2018). In addition, a recent multifactorial likelihood analysis predicted this variant to be Likely Benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 25479140, 28283652, 30254663, 29884841, 29394989, 31131967, 31131559). ClinVar contains an entry for this variant (Variation ID: 38222). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (9 clinical laboratories) and as likely benign (1 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 3081 in gene BRCA2
Functional Summary
The BRCA2 V3081A variant has been functionally characterized and is likely neutral. In vitro studies using a homology-directed DNA repair (HDR) assay demonstrated that the variant exhibits DNA-repair activity comparable to wildtype BRCA2, indicating no significant impact on protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.627
0.627
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.78primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP 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 loss of function (LOF) is a known mechanism of disease.' The evidence for this variant shows: NM_000059.4:c.9242T>C is a missense variant (V3081A) and not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 (Strong) is: 'predicted missense substitution 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: there is no previously established pathogenic variant at codon 3081 leading to the same amino acid change. 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 data on de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 (Strong) is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect.' The evidence for this variant shows: homology‐directed DNA repair assays demonstrate DNA‐repair activity comparable to wildtype BRCA2, indicating no damaging effect. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 (Strong) is: 'The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (OR ≥4, p≤0.05).' 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 (Moderate) is: 'Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.' The evidence for this variant shows: V3081A lies within the DNA-binding domain (aa 2481–3186), but this domain is not defined as a mutational hot spot for BRCA2. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: 'Absent from controls in an outbred population (gnomAD v2.1 non-cancer, exome subset and gnomAD v3.1 non-cancer).' The evidence for this variant shows: present in gnomAD at MAF=0.0012%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'For patients with BRCA1/2-related Fanconi anemia phenotype and co-occurring variants in the same gene.' The evidence for this variant shows: no Fanconi anemia phenotype or trans observations reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 (Moderate) is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: V3081A is a missense change with no length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 (Moderate) is: 'Novel missense change at an amino acid residue where a different missense change is pathogenic.' The evidence for this variant shows: no other pathogenic missense at residue 3081 reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 (Supporting) is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 (Supporting/Moderate/Strong) is: 'Co-segregation with disease in multiple affected family members with Bayes LR thresholds.' 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 (Supporting) is: 'Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease.' The evidence for this variant shows: insufficient gene‐specific constraint data. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
Cannot evaluate PP3: VCEP guidelines require 'BayesDel no-AF score ≥0.30 and predicted impact via protein change within a functional domain.' The evidence for this variant shows: BayesDel no-AF score is not available. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Phenotype with combined multifactorial likelihood data reaching LR≥2.08.' The evidence for this variant shows: no individual or family phenotype likelihood data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 (Supporting) is: 'Reputable source reports variant as pathogenic without available evidence.' The evidence for this variant shows: ClinVar entries include VUS and benign, no consensus pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 (Stand Alone) is: 'Filter allele frequency >0.1% in gnomAD non-cancer populations.' The evidence for this variant shows: MAF=0.0012% (<0.1%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 (Strong) is: 'Filter allele frequency >0.01% in gnomAD non-cancer populations.' The evidence for this variant shows: MAF=0.0012% (0.0012%<0.01%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Observed in healthy adult individuals without Fanconi anemia phenotype, with point-based system.' The evidence for this variant shows: no healthy adult cohort assessment. Therefore, this criterion is not applied.
BS3
BS3 (Strong)
According to VCEP guidelines, the rule for BS3 (Strong) is: 'Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined.' The evidence for this variant shows: HDR assay demonstrates DNA-repair activity comparable to wildtype, indicating no damaging effect. Therefore, this criterion is applied at Strong strength.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 (Strong) is: 'Lack of segregation in affected members (Bayes LR≤0.05).' The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1_Strong is: 'Silent, missense or in-frame indel outside a clinically important functional domain and no splicing predicted (SpliceAI ≤0.1).' The evidence for this variant shows: V3081A lies inside the DNA-binding domain. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 (Supporting) is: 'Observed in trans with a pathogenic variant for a dominant disorder.' The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 (Supporting) is: 'In-frame indels in repetitive regions.' The evidence for this variant shows: this is a missense change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
Cannot evaluate BP4: VCEP guidelines require 'BayesDel no-AF score ≤0.18 AND SpliceAI ≤0.1 within a functional domain.' The evidence for this variant shows: BayesDel no-AF score is not available. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 (Supporting) is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no co-occurrence data with pathogenic variants in other genes. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 (Supporting) is: 'Reputable source reports variant as benign without available evidence.' The evidence for this variant shows: ClinVar submissions are mixed with VUS and benign, but no single reputable consensus. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Silent or intronic variants outside splice sites with no predicted splicing impact.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.