BRCA2 c.7877G>C, p.Trp2626Ser
NM_000059.4:c.7877G>C
Variant of Uncertain Significance (VUS)
This variant has only one Moderate (PM5) and two Supporting (PM2, BP4) criteria and lacks additional pathogenic or benign evidence. Per ACMG/VCEP rules, this evidence combination yields a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PM5
BP4
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.7877G>C
Protein Change
W2626S
Location
Exon 17
(Exon 17 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2626 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.7877G>C
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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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 2626 in gene BRCA2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 5.50primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies only to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, multi-exon deletion) in BRCA2. The evidence for this variant shows: W2626S is a missense change, not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies when the variant results in the same amino acid change as a previously established pathogenic variant. The evidence for this variant shows: no other nucleotide change yielding W2626S has been classified pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for a confirmed de novo occurrence (maternity and paternity confirmed). The evidence for this variant shows: no de novo testing or parental confirmation data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires well-established functional studies demonstrating a damaging effect. The evidence for this variant shows: no in vitro or in vivo functional assays have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies when case-control data show a significant increase in prevalence among affected individuals. The evidence for this variant shows: no case-control or prevalence data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hotspots or well-established functional domains without benign variation. The evidence for this variant shows: although W2626 lies within the BRCA2 DNA-binding domain, this position is not defined as a mutational hotspot. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "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: it is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is not found in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies for biallelic variants in BRCA2-related Fanconi Anemia with defined phenotype criteria. 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, PM4 applies to protein length changes (in-frame indels or stop-loss). The evidence for this variant shows: W2626S is a missense change with no length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: "A novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: at amino acid residue 2626, a different missense variant has been classified as pathogenic. Therefore, this criterion is applied at Moderate strength because the residue is known to harbor pathogenic missense changes.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies for assumed de novo occurrences without confirmation. The evidence for this variant shows: no de novo information available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies for co-segregation with disease in multiple affected family members. The evidence for this variant shows: no family segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies for missense variants in a gene with low rate of benign variation where missense is a common mechanism. The evidence for this variant shows: BRCA2 has both benign and pathogenic missense variants; no gene-specific threshold met. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies for missense variants inside a clinically important functional domain with BayesDel no-AF score ≥0.30 or predicted splicing impact (SpliceAI ≥0.2). The evidence for this variant shows: mixed in silico predictions and SpliceAI = 0.03. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies when patient phenotype is highly specific for BRCA2-related disease, based on multifactorial likelihood data. The evidence for this variant shows: no phenotype or multifactorial likelihood data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source classifies the variant as pathogenic. The evidence for this variant shows: not found in ClinVar or other expert-curated databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies when allele frequency is above 0.1% in appropriate population databases. The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies when allele frequency is above 0.01% but below BA1 threshold. The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when variant is observed in healthy adults without recessive disease features. The evidence for this variant shows: no such observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies for well-established functional studies showing no damaging effect. The evidence for this variant shows: no functional assays performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for lack of segregation in affected family members. The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense variants outside a clinically important functional domain with no splicing impact. The evidence for this variant shows: variant lies inside the DNA-binding domain. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in trans with a pathogenic variant in a dominant disorder. The evidence for this variant shows: no trans observations reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: W2626S is a missense, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense or in-frame variants inside a clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF ≤0.18 AND SpliceAI ≤0.1)." The evidence for this variant shows: SpliceAI = 0.03 and in silico predictors overall suggest no impact. Therefore, this criterion is applied at Supporting strength because no deleterious impact is predicted.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies when variant is found in a case with an alternate molecular basis for disease. The evidence for this variant shows: no co-occurrence with another pathogenic variant reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source classifies the variant as benign. The evidence for this variant shows: no such classification exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants with no predicted splicing impact. The evidence for this variant shows: W2626S is a missense variant. Therefore, this criterion is not applied.