Submissions for variant NM_007294.4(BRCA1):c.807G>A (p.Leu269=)

gnomAD frequency: 0.00022  dbSNP: rs149867679

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)	RCV000409357	SCV000578001	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 0.0012 (African), derived from ExAC (2014-12-17).
GeneDx	RCV000123890	SCV000167236	benign	not specified	2014-02-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162520	SCV000212914	likely benign	Hereditary cancer-predisposing syndrome	2014-06-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001084959	SCV000252823	benign	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000409357	SCV000488501	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000463712	SCV000540983	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162520	SCV000688665	likely benign	Hereditary cancer-predisposing syndrome	2016-05-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758848	SCV000887735	benign	not provided	2023-06-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162520	SCV002537907	likely benign	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123890	SCV004026805	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000123890	SCV000591302	benign	not specified		no assertion criteria provided	clinical testing	The p.Leu269Leu variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, and is listed in dbSNP database (rs149867679) with a MAF score of 0.001. It was also reported in 1/111260 proband chromosomes of an individual from a HBOC family, and classified as a polymorphism in the study by Myriad; although no control chromosomes were tested to establish the variant's frequency in the general population (Judkins_2005). In addition, the variant was also identified in the UMD (x1), Exome Server and BOCs databases. In summary, based on the above information, the variant is classified as benign.