Submissions for variant NM_000059.4(BRCA2):c.4157A>T (p.Asp1386Val)

dbSNP: rs431825316

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001021967	SCV001183648	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-22	criteria provided, single submitter	clinical testing	The p.D1386V variant (also known as c.4157A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 4157. The aspartic acid at codon 1386 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001021967	SCV001339937	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1386 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 been detected in individuals affected with BRCA2-associated cancers and/or relevant family history (Color internal data). This variant has been identified in 1/239924 chromosomes 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854445	SCV002177144	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-02	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: 96803). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs431825316, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1386 of the BRCA2 protein (p.Asp1386Val).
University of Washington Department of Laboratory Medicine, University of Washington	RCV001021967	SCV003848731	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	RCV004804082	SCV005424422	uncertain significance	BRCA2-related cancer predisposition	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1386 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/239924 chromosomes 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.
Sharing Clinical Reports Project (SCRP)	RCV000082924	SCV000114998	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing