BRCA2 c.8880_8883del, p.Gln2960HisfsTer15
NM_000059.4:c.8880_8883del
Pathogenic
This BRCA2 frameshift variant, c.8880_8883del (Q2960Hfs*15), meets PVS1 (Very Strong), PS3 (Strong), PM2 (Supporting), and PM5 (Supporting) under VCEP guidelines. The accumulated evidence of loss of function in a LOF‐sensitive gene, damaging functional assays, absence from controls, and precedent for pathogenic PTCs supports a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PM5
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.8880_8883del
Protein Change
Q2960Hfs*15
Location
Exon 22
(Exon 22 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 2960: Q2960K
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.8880_8883del
Active Tracks
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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
ClinVar reports other pathogenic variants at position 2960: Q2960K
PM5 criterion applied.
Functional Summary
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.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Supporting) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
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 measured by quantitative analysis." No family segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.