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 Q2960Hfs*15 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, contributing to an increased risk of developing certain cancers.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 309 bp |
| Donor Loss (DL) | 0.0 | 488 bp |
| Acceptor Gain (AG) | 0.0 | -113 bp |
| Donor Gain (DG) | 0.0 | 43 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 (Very Strong Strength) 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 is a known mechanism of disease." The evidence shows this variant is a frameshift (c.8880_8883del) resulting in Q2960Hfs*15 and predicted to cause truncation with loss of critical 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, the rule for PS1 (Strong Strength) is: "Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant has the same amino acid change." The evidence shows this variant is a frameshift/truncation, not a missense substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 (Strong Strength) is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There are no data on de novo occurrence or parental testing for this variant. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 (Strong Strength) is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence shows experimental studies indicating that Q2960Hfs*15 truncates the C-terminal DNA binding domain, disrupts nuclear localization, and impairs homologous recombination. Therefore, this criterion is applied at Strong strength because well-established functional assays demonstrate a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 (Strong Strength) is: "The prevalence of the variant in affected individuals is significantly increased compared to controls (case–control data with OR ≥4 and p ≤0.05)." No case–control or cohort data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 (Moderate Strength) is: "Located in a mutational hot spot or well-established functional domain without benign variation." This variant is a truncating frameshift, not a missense or in-frame change within a specific domain hotspot. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 (Supporting Strength) is: "Absent from controls in an outbred population (gnomAD v2.1 non-cancer exomes and v3.1 non-cancer genomes)." The evidence shows this variant is not present in gnomAD. Therefore, this criterion is applied at Supporting strength because it is absent from large population datasets.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 (Supporting/Moderate/Strong) involves observing variants in trans with another pathogenic variant in patients with a BRCA2-related Fanconi Anemia phenotype. There are no data on co-occurrence or Fanconi Anemia phenotype. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 (Moderate Strength) is: "Protein length changes due to in-frame deletions/insertions in non-repeat regions." This variant is a frameshift/truncation, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Supporting)
According to VCEP guidelines, the rule for PM5 (Supporting Strength) is: "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence shows Q2960Hfs*15 introduces a PTC and other pathogenic truncating variants have been reported in BRCA2 exons. Therefore, this criterion is applied at Supporting strength because it is a novel PTC in an exon with known pathogenic PTCs.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 (Moderate Strength) is: "Assumed de novo, but without confirmation of paternity and maternity." No de novo or parental data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 (Supporting/Moderate/Strong) is: "Co-segregation with disease in multiple affected family members measured by quantitative analysis." No family segregation data are provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 (Supporting Strength) is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." This variant is a frameshift/truncation, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 (Supporting Strength) is: "Missense or in-frame indel predicted deleterious by multiple computational tools or predicted splicing impact (SpliceAI ≥0.2)." This variant is a frameshift/truncation and not evaluated by missense/splice predictors. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 (Supporting/Moderate/Strong) is: "Patient’s phenotype or family history highly specific for a disease with a single genetic etiology." No individual phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 (Supporting Strength) is: "Reputable source reports variant as pathogenic without available evidence." No such external report is available. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 (Stand-Alone) is: "Allele frequency >0.1% in gnomAD non-cancer populations." The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 (Strong Strength) is: "Filter allele frequency >0.01% in gnomAD non-cancer populations." The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 (Supporting/Moderate/Strong) is: "Observed in healthy individuals without Fanconi Anemia phenotype." No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 (Strong Strength) is: "Well-established functional studies show no damaging effect." Functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 (Supporting/Moderate/Strong) is: "Lack of segregation in affected family members." No segregation data are provided. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 (Strong Strength) is: "Missense or in-frame indel outside key functional domains with no splicing effect." This is a frameshift/truncation. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 (Supporting Strength) is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene." No such data exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 (Supporting Strength) is: "In-frame indel in a repetitive region without functional impact." This is a frameshift/truncation. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 (Supporting Strength) is: "Missense or in-frame indel inside key domains with no predicted impact (BayesDel ≤0.18 and SpliceAI ≤0.1)." This is a frameshift/truncation. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 (Supporting/Moderate/Strong) is: "Variant found in a case with an alternate molecular basis for disease." No such co-occurrence data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 (Supporting Strength) is: "Reputable source reports variant as benign without evidence." No such report exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 (Supporting/Strong) is: "Silent or intronic variant with no splicing impact." This variant is a frameshift/truncation. Therefore, this criterion is not applied.