Submissions for variant NM_007294.4(BRCA1):c.2123C>A (p.Ser708Tyr)

gnomAD frequency: 0.00003  dbSNP: rs80357182

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129531	SCV000184307	likely benign	Hereditary cancer-predisposing syndrome	2019-04-22	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	RCV000314335	SCV000329124	uncertain significance	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Also known as 2242C>A; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12531920, 15385441, 16267036, 26689913, 27062684, 31131967, 20858050, 28529006, 31409081, 32546644, 32377563, 15343273, 29884841, 35402282)
Color Diagnostics, LLC DBA Color Health	RCV000129531	SCV000910913	likely benign	Hereditary cancer-predisposing syndrome	2016-11-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193139	SCV001361783	likely benign	not specified	2022-04-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2123C>A (p.Ser708Tyr) results in a non-conservative amino acid change in 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 6.8e-05 in 251170 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2123C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Judkins_2005, Coulet_2010, Azzollini_2016). At-least one report of this variant co-occurring with a pathogenic variant (c.2062C>T, p.Gln688*) in the PTCH1 gene as an alternate molecular basis of disease in an individual with Gorlin syndrome has been reported (Paulo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least two publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had comparable homology-directed repair (HDR) activity to the wild type (Lu_2015) and a neutral impact in homologous recombination repair complementation assays (Bouwman_2020). Seven ClinVar submissons from clinical diagnostic laboratories (evaluation after 2014) cites the variant four times as uncertain significance and thrice as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709482	SCV001696861	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000314335	SCV002047270	uncertain significance	not provided	2023-10-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129531	SCV002538096	likely benign	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193139	SCV002551023	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129531	SCV003849482	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).
Sharing Clinical Reports Project (SCRP)	RCV000031028	SCV000053622	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2009-04-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031028	SCV000144307	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000031028	SCV004228341	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	PP4(Supporting)+BS1(Strong)+BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV000031028	SCV004244101	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758602	SCV005362546	likely benign	BRCA1-related disorder	2023-09-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).