Submissions for variant NM_007294.4(BRCA1):c.4729T>C (p.Ser1577Pro)

gnomAD frequency: 0.00004  dbSNP: rs80356909

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048643	SCV000076656	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131514	SCV000186508	likely benign	Hereditary cancer-predisposing syndrome	2018-12-05	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	RCV000858856	SCV000209975	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27383479, 28288110, 23704879, 19016756, 17100994, 16949048, 12496477, 19491284, 22217648, 16455195, 27124784, 30415210, 28111427, 30765603, 31131967, 28781887)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858856	SCV000605890	benign	not provided	2020-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212185	SCV000699168	benign	not specified	2020-10-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4729T>C (p.Ser1577Pro) 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 5.6e-05 in 251842 control chromosomes, predominantly at a frequency of 0.00054 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (HBOC) Syndrome (0.001). However, in certain East Asian subpopulations the variant was observed with an even higher occurrence, e.g. in the Japanese control population it occurred with a frequency of 0.0055 (jMorp database), suggesting a benign role for the variant. The variant, c.4729T>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, as well as in several unaffected controls, who were almost exclusively of East Asian origin. Two recent case-control association studies, involving breast cancer patients and controls of Korean- (Park_2017) and Japanese ancestry (Momozawa_2018), found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of these studies classified that the variant as likely benign/benign, respectively. Co-occurrences with other pathogenic variants have been reported (ATM c.7456C>T (p.Arg2486X) in Ohmoto_2018; and BRCA2 c.6952C>T (p.Arg2318X), and BRCA2 c.6486_6489delACAA (p.Lys2162AsnfsX5) in two internal LCA samples), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had a slightly stronger transcriptional activity than the wild type; therefore, authors classified the variant as "not likely pathogenic" (Woods 2016). Six other 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 (1x) / likely benign (5x). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000131514	SCV000910806	benign	Hereditary cancer-predisposing syndrome	2016-01-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000077585	SCV001140512	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000858856	SCV001474609	likely benign	not provided	2019-10-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131514	SCV002537776	likely benign	Hereditary cancer-predisposing syndrome	2021-02-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212185	SCV002550966	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077585	SCV000109388	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-05-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077585	SCV000145167	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758630	SCV005365960	likely benign	BRCA1-related disorder	2024-08-03	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).