Submissions for variant NM_007294.4(BRCA1):c.795T>C (p.Ser265=)

gnomAD frequency: 0.00006  dbSNP: rs201441987

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112789	SCV000577994	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0031 (East Asian), derived from ExAC (2014-12-17).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082438	SCV000077153	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163599	SCV000214162	likely benign	Hereditary cancer-predisposing syndrome	2014-09-30	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.
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000496381	SCV000586871	likely benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587508	SCV000600437	benign	not provided	2022-11-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163599	SCV000683358	likely benign	Hereditary cancer-predisposing syndrome	2016-02-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587508	SCV000699302	likely benign	not provided	2017-02-21	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 795T>C (p.Ser265Ser) variant causes a synonymous change involving the alteration of a conserved nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 27/121032 (1/4482), predominantly in the East Asian cohort, 27/8652 (1/320), which does exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. Therefore, suggesting the variant is a benign polymorphism found in population(s) of East Asian origin. A functional study, Raponi_2012 reports that the variant could influence the use of an alternative splice site reducing the D(11a) isoform, however, this functional experiment alone is not sufficient evidence to suggest pathogenicity. In addition, Thirthagiri_2008 and Judkins_2005, along with multiple clinical diagnostic laboratories classify the variant as "likely benign/benign/polymorphism." Taken together, this variant is classified as a "likely benign."
Counsyl	RCV000112789	SCV000786089	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-02-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163599	SCV002537898	likely benign	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112789	SCV000145685	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-09-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554692	SCV004763714	likely benign	BRCA1-related disorder	2022-10-26	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).