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
OpenThe p.V2687F variant (also known as c.8059G>T), located in coding exon 17 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8059. The valine at codon 2687 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med., 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). Based on internal structural assessment, this alteration disrupts the structure of the OB1 domain, near the interface with DSS (Yang H et al. Science, 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
This variant is present in population databases (rs80359044, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033, 21520333). ClinVar contains an entry for this variant (Variation ID: 52491). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function. This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2687 of the BRCA2 protein (p.Val2687Phe). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29884841, 33609447). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
"This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: BRCA2V2687FBRCA2V2687FSomaticNCBI Gene:675|Show additional gene information Variant OverviewBRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.The BRCA2 V2687F mutation is likely oncogenic.Hide mutation effect description The BRCA2 V2687F mutation is located in the DNA-binding domain of the protein (PMID: 35736817). In vitro studies have demonstrated that this mutation is inactivating as measured by loss of homology-directed DNA repair (HDR) in an in vitro HDR assay (PMID: 35736817). Germline BRCA2 V2687F mutations are considered likely pathogenic by the ACMG framework classification (PMID: 35736817). JAX-CKB: No results found
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -82 bp |
| Donor Loss (DL) | 0.01 | 272 bp |
| Acceptor Gain (AG) | 0.0 | 154 bp |
| Donor Gain (DG) | 0.0 | 8 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PS3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
BP4 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)