Submissions for variant NM_007294.4(BRCA1):c.2346T>A (p.Ser782Arg)

dbSNP: rs1555589837

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488709	SCV000698942	uncertain significance	not specified	2023-12-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2346T>A (p.Ser782Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250738 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2346T>A has been reported in at-least one individual from a study that offered hereditary cancer panel test to a cohort of 132 patients and was classified as VUS (example: Yorczyk_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25318351). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000588839	SCV000806913	uncertain significance	not provided	2017-03-21	criteria provided, single submitter	clinical testing
Invitae	RCV000693241	SCV000821101	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185320	SCV001351508	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 782 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been reported in a sample referred for hereditary cancer screening (PMID 25318351). This variant has not been identified 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001185320	SCV003847738	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).