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
OpenMissense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 39 bp |
| Donor Loss (DL) | 0.0 | -128 bp |
| Acceptor Gain (AG) | 0.0 | 186 bp |
| Donor Gain (DG) | 0.0 | 128 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PVS1, '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: it is a missense substitution (p.V891A), not a null variant. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines for PS1, 'Strong 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 (SpliceAI≤0.1)).' The evidence for this variant shows: no previously established pathogenic variant results in p.V891A. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines for PS2, 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no de novo inheritance data available. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines for PS3, 'Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect.' The evidence for this variant shows: no functional studies have been performed for p.V891A. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines for PS4, 'Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p≤0.05 and OR≥4).' The evidence for this variant shows: no case-control or family prevalence data available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines for PM1, 'Moderate Apply for missense or in-frame variants located in a clinically important functional domain.' The evidence for this variant shows: p.V891A is outside the BRCA2 PALB2-binding domain (aa 10–40) and DNA-binding domain (aa 2481–3186). Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines for PM2, 'Supporting Absent from controls in an outbred population, from gnomAD v2.1 and v3.1.' The evidence for this variant shows: it is not found in gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines for PM3, 'Supporting Apply for patient with phenotype consistent with BRCA1-/BRCA2-related Fanconi Anemia and co-occurrence of variants.' The evidence for this variant shows: no Fanconi Anemia phenotype or compound heterozygosity data. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4, 'Protein length changes as a result of in-frame indels or stop-loss variants.' The evidence for this variant shows: it is a missense substitution, not an in-frame indel or stop-loss. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5, 'Strong/Moderate/Supporting applied only to protein termination codon (PTC) variants where a different proven pathogenic PTC variant has been seen.' The evidence for this variant shows: p.V891A is a missense, not a PTC. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6, 'Assumed de novo but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines for PP1, 'Co-segregation with disease in multiple affected family members measured by quantitative analysis.' The evidence for this variant shows: no family segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2, 'Missense variant in a gene with a low rate of benign missense variants.' The evidence for this variant shows: BRCA2 has many benign and pathogenic missense variants and no specific PP2 recommendation. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PP3, 'Supporting Apply for missense variants inside a functional domain with BayesDel no-AF ≥0.30 or splicing impact SpliceAI≥0.2.' The evidence for this variant shows: SpliceAI=0.0 and computational protein predictors (REVEL=0.25) below thresholds. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines for PP4, 'Use only to capture combined LR based on multifactorial clinical data.' The evidence for this variant shows: no multifactorial likelihood data. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5, 'Reputable source reports variant as pathogenic.' The evidence for this variant shows: ClinVar lists it as VUS, not pathogenic. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1, 'Stand Alone Filter allele frequency above 0.001 in gnomAD.' The evidence for this variant shows: allele frequency = 0%, below threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1, 'Strong Filter allele frequency above 0.0001 in gnomAD.' The evidence for this variant shows: allele frequency = 0%, below threshold. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines for BS2, 'Strong Applied in absence of Fanconi Anemia features.' The evidence for this variant shows: no healthy adult cohort data assessed for FA phenotype. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3, 'Strong Well-established functional studies show no damaging effect.' The evidence for this variant shows: no such functional studies. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines for BS4, 'Strong Lack of segregation in affected family members.' The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1 (Strong)
According to VCEP guidelines for BP1, 'Strong Apply BP1_Strong for missense variants outside a clinically important functional domain AND no splicing predicted (SpliceAI≤0.1).' The evidence for this variant shows: p.V891A is outside known functional domains and SpliceAI=0.0. Therefore, BP1 is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines for BP2, 'Observed in trans with a pathogenic variant for a fully penetrant dominant disorder.' The evidence for this variant shows: no in trans observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3, 'In-frame indel in a repetitive region without a known function.' The evidence for this variant shows: not an in-frame indel. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines for BP4, 'Supporting Missense variants inside functional domain with no predicted impact.' The evidence for this variant shows: it is outside functional domains. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines for BP5, 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such co-occurrence data. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines for BP6, 'Reputable source reports variant as benign.' The evidence for this variant shows: no such report. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines for BP7, 'Supporting Silent or intronic variants outside splice sites if BP4 met.' The evidence for this variant shows: it is missense. Therefore, BP7 is not applied.