Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_007294.4 | MANE Select | 7088 nt | 114–5705 |
| NM_007294.2 | Alternative | 7191 nt | 201–5792 |
| NM_007294.3 | RefSeq Select | 7224 nt | 233–5824 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe p.V11G variant (also known as c.32T>G), located in coding exon 1 of the BRCA1 gene, results from a T to G substitution at nucleotide position 32. The valine at codon 11 is replaced by glycine, an amino acid with dissimilar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay. (Findlay GM et al. Nature, 2018 10;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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.
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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 245973). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 11 of the BRCA1 protein (p.Val11Gly). This variant is not present in population databases (gnomAD no frequency).
The BRCA1 c.32T>G (p.Val11Gly) variant has been reported in the published literature in individuals affected with prostate cancer (PMID: 36922933 (2022)), hereditary breast and ovarian cancer (PMID: 30702160 (2019)), and other BRCA1-associated cancers (PMID: 31853058 (2020)). Functional studies demonstrated that this variant lost functional activity in large-scale, high-throughput multiplexed assays (PMID: 30209399 (2018), PMID: 39627863 (2024), PMID: 34793697 (2021), PMID: 35659930 (2022)). The variant is located in a region that is considered important for protein function and/or structure (PMID: 11573085 (2001)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
"This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (1 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: BRCA1V11GBRCA1V11GSomaticNCBI Gene:672|Show additional gene information Variant OverviewBRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.The BRCA1 V11G mutation has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown.Hide mutation effect description The BRCA1 V11G mutation has not specifically been reviewed by the OncoKB team. However, the mutation effect description for BRCA1 V11A, an alternate allele of BRCA1 V11G, is: The BRCA1 V11A mutation is of inconclusive function. In a study of BRCA1 association with BRCA1-associated RING domain-1 protein (BARD1), the V11A mutation was found to significantly reduce complex reassembly (PMID: 18493658), but the consequences of this reduction are unknown. 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 | -26 bp |
| Donor Loss (DL) | 0.0 | 2 bp |
| Acceptor Gain (AG) | 0.03 | 50 bp |
| Donor Gain (DG) | 0.04 | -48 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
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)