Submissions for variant NM_000059.4(BRCA2):c.4977C>T (p.Ser1659=)

gnomAD frequency: 0.00009  dbSNP: rs45484897

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495225	SCV000579051	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	RCV000160226	SCV000210610	benign	not specified	2014-08-12	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	RCV000163195	SCV000213716	likely benign	Hereditary cancer-predisposing syndrome	2014-10-09	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	RCV001085635	SCV000253020	benign	Hereditary breast ovarian cancer syndrome	2025-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163195	SCV000683664	benign	Hereditary cancer-predisposing syndrome	2015-12-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589985	SCV000694818	benign	not provided	2016-09-02	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.4977C>T (p.Ser1659Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant, and 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. This variant was found in 14/118706 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0002136 (14/65542). This frequency is slightly less than the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting the variant could potentially be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. Additionally, the variant of interest has only been reported, to our knowledge, in one publication suggesting it was a somatic occurrence in a cell line, although information is limited. Furthermore, multiple reputable clinical laboratories have cited the variant with a classification of "likely benign/benign." In addition, a reputable database cites the variant to co-occur with another potentially pathogenic BRCA2 variant, c.6515C>A (p.Ser2172X) and in two LabCorp specimens, one with BRCA1 (p.K653fs*47) and one with a CHEK2 (c.1100delC), both of which are pathogenic. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589985	SCV000887832	likely benign	not provided	2022-09-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589985	SCV001472682	likely benign	not provided	2023-11-13	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001085635	SCV002515114	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000163195	SCV002533917	likely benign	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000589985	SCV004701285	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160226	SCV005090038	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000163195	SCV000787934	likely benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000495225	SCV004243646	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing