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
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -247 bp |
| Donor Loss (DL) | 0.0 | -294 bp |
| Acceptor Gain (AG) | 0.0 | 115 bp |
| Donor Gain (DG) | 0.0 | -140 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Null variant (nonsense, frameshift, splice site, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (p.P3320A), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change with same amino acid change.' The evidence for this variant shows: there is no previously established pathogenic variant causing p.P3320A. 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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied.
PS3 (Not Applied)
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: no functional characterization has been performed. Therefore, this criterion is not applied.
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.' The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Moderate: Variant located in a mutational hot spot and/or well-studied functional domain without benign variation.' The evidence for this variant shows: p.P3320A is outside defined BRCA2 functional domains (PALB2 binding aa 10–40; DNA-binding aa 2481–3186). 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.' The evidence for this variant shows: not found in population databases (gnomAD MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Apply for patient with phenotype consistent with BRCA2-related Fanconi Anemia and co-occurring variants in the same gene.' The evidence for this variant shows: no information on FANCONI anemia phenotype or co-occurring variants. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in-frame deletions/insertions in a non-repetitive region.' The evidence for this variant shows: it is a single amino acid substitution, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence for this variant shows: no other pathogenic variant reported at codon 3320. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data available. 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.' The evidence for this variant shows: BRCA2 has both benign and pathogenic missense variants; no specific data supports PP2. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Supporting: Missense variant inside a functional domain with predicted impact via protein change (BayesDel ≥0.30).’ The evidence for this variant shows: it is outside defined domains and REVEL=0.12, CADD=2.29, SpliceAI=0. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: 'Supporting: Phenotype specificity based on multifactorial likelihood data.' The evidence for this variant shows: no patient phenotype or multifactorial data provided. 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.' The evidence for this variant shows: 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.' The evidence for this variant shows: MAF=0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong: Filter allele frequency >0.01% in gnomAD.' The evidence for this variant shows: MAF=0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in healthy adult individuals in absence of Fanconi Anemia features.' The evidence for this variant shows: no healthy adult data. 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: no functional studies. 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 (Strong)
According to VCEP guidelines, the rule for BP1 is: 'Strong: Silent or missense variant outside functional domain and no splicing predicted (SpliceAI ≤0.1).' The evidence for this variant shows: p.P3320A is outside defined domains and SpliceAI=0. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observation of the variant in trans with a pathogenic variant for a dominant disorder.' 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 deletions/insertions in repetitive region without known function.' The evidence for this variant shows: it is a single amino acid substitution, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting: Missense variant inside functional domain with no predicted impact.' The evidence for this variant shows: it is outside defined domains, despite benign computational scores. Therefore, this criterion is not applied under gene-specific BP4.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: 'Supporting: Observation in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no co-observation with other 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.' The evidence for this variant shows: not found in any such source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting: Silent or intronic variant outside splice motifs with no predicted impact, IF BP4 met.' The evidence for this variant shows: it is a missense substitution, not eligible for BP7. Therefore, this criterion is not applied.