ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1184G>T (p.Trp395Leu)

dbSNP: rs886040347
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001236953 SCV001409696 uncertain significance Hereditary breast ovarian cancer syndrome 2022-09-09 criteria provided, single submitter clinical testing 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 of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 962996). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 395 of the BRCA2 protein (p.Trp395Leu).
University of Washington Department of Laboratory Medicine, University of Washington RCV003158593 SCV003849894 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health RCV004004869 SCV004837505 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-10-06 criteria provided, single submitter clinical testing This missense variant replaces tryptophan with leucine at codon 395 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV003158593 SCV005097586 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-17 criteria provided, single submitter clinical testing The p.W395L variant (also known as c.1184G>T), located in coding exon 9 of the BRCA2 gene, results from a G to T substitution at nucleotide position 1184. The tryptophan at codon 395 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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