Submissions for variant NM_007294.4(BRCA1):c.1155G>T (p.Trp385Cys)

dbSNP: rs876660558

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226202	SCV000289738	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-09	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 385 of the BRCA1 protein (p.Trp385Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 240771). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003114399	SCV000296436	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	The BRCA1 c.1155G>T (p.Trp385Cys) variant has been reported in the published literature to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). Additionally, the variant was reported in a study including men affected with prostate cancer and reportedly healthy individuals, however the study does not specify if the individuals were affected or not (PMID: 32832836 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV000509631	SCV000607794	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-27	criteria provided, single submitter	clinical testing	The p.W385C variant (also known as c.1155G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 1155. The tryptophan at codon 385 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000509631	SCV000682940	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781000	SCV000918745	uncertain significance	not specified	2018-01-12	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1155G>T (p.Trp385Cys) variant involves the alteration of a conserved nucleotide, is located in serine-rich domain of the protein (InterPro) and is predicted to be damaging by 5/5 in silico tools. This variant was found in 4/265666 control chromosomes at a frequency of 0.0000151 (gnomAD and FLOSSIES db), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The FLOSSIES db includes 7325 European Americans and 2559 African Americans aged over 70 yrs and this variant was only reported in this database. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Based on the currently available information, the variant is classified as a variant of uncertain significance (VUS).
GeneDx	RCV003114399	SCV003798605	uncertain significance	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1274G>T; This variant is associated with the following publications: (PMID: 10426999, 20215511, 15343273, 9926942, 9582019, 11521194)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509631	SCV003846133	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).