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 R3005Ifs*12 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.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.23 | -5 bp |
| Donor Loss (DL) | 0.01 | 123 bp |
| Acceptor Gain (AG) | 0.02 | 225 bp |
| Donor Gain (DG) | 0.0 | 107 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
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 is a known mechanism of disease." The evidence for this variant shows: NM_000059.4:c.9014_9015del (R3005Ifs*12) is a frameshift predicted to result in a truncated BRCA2 protein lacking critical functional domains. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in BRCA2, a gene where loss-of-function is a known mechanism of disease.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing)." The evidence for this variant shows: it is a frameshift, not a missense or synonymous variant matching a previously classified pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
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 parental origin or de novo occurrence. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: functional studies demonstrate that R3005Ifs*12 truncates BRCA2, impairing nuclear localization and homologous recombination. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control studies; p≤0.05 and OR≥4)." The evidence for this variant shows: no case-control or cohort data available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: it is a frameshift variant, not a missense or in-frame variant in a defined hot spot. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in gnomAD v2.1 and v3.1 non-cancer populations with adequate coverage." The evidence for this variant shows: it is not present in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Apply for BRCA2-related Fanconi Anemia phenotype with co-occurrent variants; assign points based on phenotype and co-occurrence." The evidence for this variant shows: no Fanconi Anemia phenotype or co-occurrence data. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 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: it is a frameshift leading to premature truncation, not an in-frame event. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows: insufficient data on other PTC variants in the same exon. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data at all. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members, weighted by Bayes score." The evidence for this variant shows: no familial segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 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: it is a frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting in silico predictions for missense or splicing impact (BayesDel ≥0.30 or SpliceAI ≥0.2)." The evidence for this variant shows: in silico tools do not predict a significant splicing effect (SpliceAI max score 0.23) and it is not a missense variant. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Phenotype specificity criteria based on multifactorial likelihood data for breast cancer." The evidence for this variant shows: no detailed patient phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: it is not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone allele frequency >0.1% in gnomAD non-cancer populations." The evidence for this variant shows: absent from population databases, not exceeding threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong allele frequency >0.01% but ≤0.1% in gnomAD non-cancer populations." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Applied in absence of recessive disease features (Fanconi Anemia phenotype)." The evidence for this variant shows: no data on absence of Fanconi Anemia phenotype. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: "Silent or missense outside functional domains with no predicted splicing impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant for which the phase is unknown." The evidence for this variant shows: no such co-occurrence data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertion/deletion in a repetitive region without known function." The evidence for this variant shows: it is a frameshift, not an in-frame change. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting benign computational evidence (BayesDel ≤0.18 and SpliceAI ≤0.1)." The evidence for this variant shows: in silico predictions do not meet benign thresholds and variant is frameshift. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Cases with pathogenic variants in two different breast–ovarian cancer risk genes have no specific phenotype." The evidence for this variant shows: no data on other co-occurring pathogenic variants. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without evidence." The evidence for this variant shows: no such benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Silent or intronic variants with no splicing impact, or missense outside functional domains for which BS3 is met." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.