Submissions for variant NM_007294.4(BRCA1):c.5086G>C (p.Val1696Leu)

dbSNP: rs80357125

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509683	SCV000608218	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-06	criteria provided, single submitter	clinical testing	The p.V1696L variant (also known as c.5086G>C), located in coding exon 16 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5086. The valine at codon 1696 is replaced by leucine, an amino acid with highly similar properties. This variant is located in the BRCT domain of the BRCA1 protein, and functional studies indicate a moderate effect on structural integrity and stability (Williams RS et al. J. Biol. Chem. 2003 Dec; 278(52):53007-16; Williams RS et al. Nat. Struct. Mol. Biol. 2004 Jun; 11(6):519-25; Glover JN, Fam. Cancer 2006; 5(1):89-93; Drikos I et al. Proteins 2009 Nov; 77(2):464-76; Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90). Another functional study found that this nucleotide substitution is functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). 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 available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513664	SCV003441931	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1696 of the BRCA1 protein (p.Val1696Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55390). 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 expected to disrupt BRCA1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 11877378, 19452558, 20516115, 28781887, 30209399, 30765603). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112494	SCV000145306	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496734	SCV000587459	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000112494	SCV001237579	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro