Submissions for variant NM_007294.4(BRCA1):c.5402G>A (p.Gly1801Asp)

gnomAD frequency: 0.00002  dbSNP: rs531210457

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132269	SCV000187352	likely benign	Hereditary cancer-predisposing syndrome	2019-07-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001719903	SCV000210218	likely benign	not provided	2020-03-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24265153, 26689913, 22752604, 30209399, 30555256, 33087888)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461010	SCV000549327	benign	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132269	SCV000910793	benign	Hereditary cancer-predisposing syndrome	2016-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160007	SCV001337979	benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5402G>A (p.Gly1801Asp) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5402G>A has been reported in the literature in individuals affected with breast and ovarian cancer (e.g. Mehta_2018, Manie_2016) and as an unclassified variant in at-least two relatives of patients with early-onset breast cancer (Juwle_2012) without strong evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report experimental evidence evaluating an impact on homology directed repair (HDR) activity (example, Lu_2015, Findlay_2018). Both studies no impact of this variant on HDR activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000132269	SCV002537850	likely benign	Hereditary cancer-predisposing syndrome	2021-01-27	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV001073171	SCV004817553	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-03	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV004584198	SCV005068361	uncertain significance	Inherited ovarian cancer (without breast cancer)	2024-05-06	criteria provided, single submitter	clinical testing	BS3_Strong
Brotman Baty Institute, University of Washington	RCV001073171	SCV001238682	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro