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
OpenData used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (22.1) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.98 and an overall classification of pathogenic (PS3_strong). Data not used in classification: There are additional reports of this variant in ClinVar (2), BIC (1), and BRCA2 LOVD (1).
The p.W2788R variant (also known as c.8362T>C), located in coding exon 18 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8362. The tryptophan at codon 2788 is replaced by arginine, an amino acid with dissimilar properties. This variant was non-functional in multiple homology-directed DNA repair (HDR) assays (Guidugli L et al. Am. J. Hum. Genet. 2018 02;102(2):233-248; Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). Based on internal structural analysis, this alteration is likely to disrupt the local structure (Ambry internal data; Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 to affect BRCA2 protein function (PMID: 29884841, 29394989). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52563). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 2788 of the BRCA2 protein (p.Trp2788Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine.
"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic 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: BRCA2W2788RBRCA2W2788RSomaticNCBI 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 W2788R mutation is likely oncogenic.Hide mutation effect description The BRCA2 W2788R mutation is located in the DNA-binding domain of the protein. Expression of this mutation in a BRCA-deficient cell line demonstrated that it is likely inactivating as measured by decreased homologous recombination (HR) DNA-repair activity in an in vitro homology-directed DNA repair (HDR) assay compared to wildtype BRCA2 and BRCA2-negative controls (PMID: 29394989). In vitro studies have demonstrated that this mutation is inactivating as measured by loss of HDR in an in vitro HDR assay (PMID: 35736817). Germline BRCA2 W2788R 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) | 0.03 | 68 bp |
| Donor Loss (DL) | 0.0 | 396 bp |
| Acceptor Gain (AG) | 0.0 | -30 bp |
| Donor Gain (DG) | 0.01 | 125 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)