Submissions for variant NM_007294.4(BRCA1):c.4084G>T (p.Asp1362Tyr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002323145	SCV002626514	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-13	criteria provided, single submitter	clinical testing	The p.D1362Y variant (also known as c.4084G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4084. The aspartic acid at codon 1362 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002323145	SCV003849265	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003645268	SCV004404201	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1362 of the BRCA1 protein (p.Asp1362Tyr). 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. Studies have shown this missense change is associated with skipping of exon 10, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 28905878; Invitae). 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 BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 1737655). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency).