Submissions for variant NM_007294.4(BRCA1):c.2245G>T (p.Asp749Tyr)

dbSNP: rs80357114

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047772	SCV000075785	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510045	SCV000607865	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The p.D749Y variant (also known as c.2245G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2245. The aspartic acid at codon 749 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in two female probands of Mexican descent with early-onset breast cancer (Calderón-Garcidueñas AL, Salud Publica Mex; 47(2):110-5; Ruiz-Flores P et al. Hum. Mutat. 2002 Dec;20(6):474-5). This alteration was also reported in a cohort of 55630 patients who underwent BRCA1 gene sequencing at a commercial laboratory and was classified as a variant of unknown significance (Judkins T et al. Cancer Res., 2005 Nov;65:10096-103). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000510045	SCV001352952	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-22	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 749 of the BRCA1 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 reported in two individuals affected with breast cancer (PMID: 12442275, 15889636). This variant has been identified in 2/251168 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284287	SCV001469989	uncertain significance	not provided	2022-10-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251168 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 16267036 (2005), 15889636 (2005), 12442275 (2002)). A multifactorial analysis study has characterized the variant as being likely benign (PMID: 31131967 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510045	SCV003847817	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111807	SCV000144355	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing