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 (2 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 | -43 bp |
| Donor Loss (DL) | 0.0 | 39 bp |
| Acceptor Gain (AG) | 0.0 | 313 bp |
| Donor Gain (DG) | 0.0 | 497 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 (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: c.6340C>T (P2114S) is a missense variant, not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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: there is no previously established pathogenic variant causing the same amino acid change P2114S. 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 de novo data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: 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 P2114S in BRCA2. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (case‐control studies; p‐value ≤0.05 and OR ≥4)." The evidence for this variant shows: no case‐control or cohort data demonstrating enrichment in affected individuals. 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: P2114S lies outside of known BRCA2 functional domains (PALB2 binding aa10–40, DNA‐binding aa2481–3186). Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent from controls in an outbred population, from gnomAD v2.1 (non‐cancer, exome only subset) and gnomAD v3.1 (non‐cancer)." The evidence for this variant shows: c.6340C>T is absent from gnomAD and other large population databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Strong Strength: Apply for patient with phenotype consistent with BRCA1‐ or BRCA2‐related Fanconi Anemia and co‐occurrent variants in the same gene." The evidence for this variant shows: no Fanconi Anemia phenotype or trans observations reported. 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: P2114S is a missense change without protein length alteration. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Strong Strength: 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: P2114S is a missense variant, not a PTC. 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 available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Strong Strength: Co‐segregation with disease in multiple affected family members (Bayes LR ≥18.7:1)." The evidence for this variant shows: no segregation data reported. 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 a low rate of benign missense variants and where missense variants are a common mechanism of disease." The evidence for this variant shows: BRCA2 has numerous missense variants, and it is unclear that benign missense are rare. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Apply PP3 for missense or in‐frame variants inside a clinically important functional domain with predicted impact via protein change (BayesDel no‐AF ≥0.30) or predicted splicing (SpliceAI ≥0.2)." The evidence for this variant shows: P2114S lies outside defined domains and SpliceAI ≤0.1. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Use only to capture combined LR based on multifactorial likelihood clinical data in breast cancer; strong if LR ≥18.7:1, moderate if LR ≥4.3:1, supporting if LR ≥2.08:1." The evidence for this variant shows: no multifactorial clinical likelihood data available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar submissions report Uncertain Significance, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Filter allele frequency (FAF) is above 0.1% in gnomAD non‐cancer populations." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Filter allele frequency (FAF) is above 0.01% in gnomAD non‐cancer populations." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Applied in absence of recessive disease features (Fanconi Anemia) with ≥4 healthy adult observations." The evidence for this variant shows: no healthy adult observation data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Well‐established functional studies show no damaging effect on protein or mRNA." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Lack of segregation in affected family members (Bayes LR ≤0.05:1)." The evidence for this variant shows: no segregation studies reported. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, the rule for BP1 is: "Strong Strength: Apply BP1 for silent substitution, missense or in‐frame variants outside a clinically important functional domain AND no splicing predicted (SpliceAI≤0.1)." The evidence for this variant shows: P2114S is a missense variant outside defined domains and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant gene, or cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows: no trans or cis observations with known pathogenic variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: P2114S is a missense change, not an in‐frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)." The evidence for this variant shows: in silico predictors (CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI) predominantly predict benign impact and SpliceAI predicts no splicing effect. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Strong Strength: Use only to capture combined LR against pathogenicity in multifactorial likelihood data." The evidence for this variant shows: no co‐observation with pathogenic variants in other breast/ovarian cancer genes. 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 available evidence." The evidence for this variant shows: no such benign reports from expert panels. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Strong/Supporting Strength: Silent or intronic variants with no predicted impact on splicing." The evidence for this variant shows: P2114S is a missense change, not silent or intronic. Therefore, this criterion is not applied.