Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000059.4 | MANE Select | 11954 nt | 200–10456 |
| NM_000059.2 | Alternative | 11386 nt | 228–10484 |
| NM_000059.3 | RefSeq Select | 11386 nt | 228–10484 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The BRCA2 S642Wfs*3 variant is a truncating mutation that results in the loss of critical protein domains, including the C-terminal DNA binding domain, nuclear localization signal, and CDK2 phosphorylation site. Experimental evidence indicates that such truncating mutations impair the nuclear localization of BRCA2, which is essential for its role in maintaining homologous recombination during the DNA damage response. This functional impairment supports a damaging effect of the variant.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -14 bp |
| Donor Loss (DL) | 0.01 | 474 bp |
| Acceptor Gain (AG) | 0.0 | 59 bp |
| Donor Gain (DG) | 0.0 | -271 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines: "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 a frameshift insertion NM_000059.4:c.1924_1925insGG resulting in S642Wfs*3, predicted to trigger nonsense‐mediated decay and truncate essential BRCA2 domains. Therefore, this criterion is applied at Very Strong strength because it is a null variant in BRCA2, a gene with LOF as a known disease mechanism.
PS1 (Not Applied)
According to VCEP guidelines: PS1 applies to missense substitutions where a previously classified pathogenic variant has the same amino acid change. The evidence for this variant shows a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines: PS2 requires confirmed de novo occurrence in a patient with the disease and no family history. No parental testing data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines: "PS3 Strong — Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows functional studies demonstrating loss of BRCA2 nuclear localization and homologous recombination impairment due to truncation. Therefore, this criterion is applied at Strong strength because well‐established functional assays support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines: "PS4 Strong — The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control studies with OR ≥4)." No case-control or cohort data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines: PM1 applies to variants in a known functional domain for missense or in-frame changes. The evidence for this variant shows a frameshift truncation. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines: "Supporting — Absent from controls in gnomAD v2.1 and v3.1." The evidence for this variant shows it is not present in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it is absent from population databases.
PM3 (Not Applied)
According to VCEP guidelines: PM3 applies to co-occurrence of variants in BRCA2-related Fanconi Anemia with phenotype data. No Fanconi anemia phenotype or co-occurrence data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines: PM4 applies to protein length changes for in-frame insertions/deletions not affecting LOF. PVS1 already addresses this frameshift LOF. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines: PM5 applies to new stop‐gain variants in an exon with a known pathogenic stop‐gain. PVS1 provides the null effect for this truncation. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines: PM6 requires assumed de novo occurrences without confirmation. No parental data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines: PP1 requires co-segregation data in affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines: PP2 applies to missense variants in genes with low benign missense variation. This is a frameshift variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines: PP3 applies to missense/in-frame variants or predicted splicing impact (SpliceAI ≥0.2). This frameshift variant is not evaluated by in silico splicing models for PP3. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines: PP4 requires a phenotype-specific multifactorial likelihood model. No detailed phenotype or multifactorial analysis is provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: PP5 applies when multiple reputable sources classify the variant as pathogenic. This variant is not present in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines: BA1 requires allele frequency >0.1% in gnomAD. The variant has MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines: BS1 requires FAF >0.01%. The variant has MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines: BS2 applies in absence of Fanconi Anemia features. No systematic phenotypic data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines: BS3 requires functional studies showing no damaging effect. Functional data demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines: BS4 requires lack of segregation in families. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines: BP1 applies to silent or missense variants outside functional domains. This is a truncating frameshift. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines: BP2 applies when variants co-occur in trans with a pathogenic variant in a gene for a dominant condition. No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: BP3 applies to in-frame deletions/insertions in repetitive regions. This is a frameshift insertion. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines: BP4 applies to missense/in-frame variants with benign computational evidence. This frameshift variant is not evaluated under BP4. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines: BP5 applies to co-occurrence with pathogenic variants in other genes. No such data are present. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines: BP6 applies to variants asserted benign by reputable sources without evidence. No such assertions exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines: BP7 applies to silent or intronic variants with no impact on splicing. This is a truncating frameshift. Therefore, this criterion is not applied.