Submissions for variant NM_000059.4(BRCA2):c.627C>T (p.Leu209=)

gnomAD frequency: 0.00003  dbSNP: rs28897704

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495212	SCV000579140	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
GeneDx	RCV000160198	SCV000210548	benign	not specified	2014-07-29	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	RCV000163068	SCV000213564	likely benign	Hereditary cancer-predisposing syndrome	2014-09-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081531	SCV000253023	benign	Hereditary breast ovarian cancer syndrome	2024-01-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163068	SCV000683765	likely benign	Hereditary cancer-predisposing syndrome	2015-07-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160198	SCV000694955	likely benign	not specified	2024-03-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000589025	SCV000805736	likely benign	not provided	2017-10-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589025	SCV002046625	benign	not provided	2021-02-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163068	SCV002536217	likely benign	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000495212	SCV001553954	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Leu209Leu variant was identified by Giacomo (Giacomo 2013) in an individual with Breast Cancer. The variant was also identified in dbSNP (ID: rs28897704) “With benign allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined; in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 2 of 121164 chromosomes (frequency: 0.0000) or 1 European (Non-Finnish) and 1 East Asian individuals, and none from a population of East Asian, Other, African, Latino, South Asian, and European (Finnish) individuals; the ClinVar database (classified as a benign variant by GeneDx and likely benign by Ambry Genetics), and UMD (1X as a 3-UV variant). The p.Leu209Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The BRCA2 p.Leu209Leu variant did not show exon skipping in functional assays combining minigene assays and analysis of patient RNA, contradicting the bioinformatics approach of using ESRseq scores to evaluate RNA hexamers as potential exonic splicing elements (Di Giacomo 2013). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.