Submissions for variant NM_000059.4(BRCA2):c.9586A>G (p.Lys3196Glu)

gnomAD frequency: 0.00004  dbSNP: rs80359228

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080657	SCV000073875	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129724	SCV000184529	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000586984	SCV000210690	likely benign	not provided	2021-01-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 26332594, 24607278, 11139248, 25556971, 21120943, 27153395, 25985138, 27062684, 23704879, 27067391, 30254663, 31131559, 32123317)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045862	SCV000538501	uncertain significance	not specified	2016-08-11	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 male breast cancer patient - multiple other publications report as nonpathogenic; ClinVar: 5 B/LB, 1 VUS
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586984	SCV000600869	likely benign	not provided	2023-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586984	SCV000695254	likely benign	not provided	2017-07-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129724	SCV000902714	benign	Hereditary cancer-predisposing syndrome	2016-07-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586984	SCV001158350	likely benign	not provided	2023-09-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586984	SCV001502178	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129724	SCV002532052	likely benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031834	SCV000054442	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031834	SCV000147670	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148420	SCV000190119	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001269375	SCV000592294	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Lys3196Glu variant was identified in 1 of 74 proband chromosomes (frequency: 0.014) from individuals or families with male breast cancer, and was not identified in 200 control chromosomes from healthy individuals (Kwiatkowska 2000); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in dbSNP (ID: rs80359228) “With uncertain significance”, with a minor allele frequency of 0.000/1 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, ClinVar database, the BIC database (8 X with unknown clinical importance), and UMD (7 X as an unknown variant). The variant was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant was identified by the Exome Variant Server project in 1 of 8600 European American alleles (frequency: 0.0001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Lys3196 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. One study (Santos 2014), found the variant co-occurring with a pathogenic BRCA2 variant c.8488-1G>A, increasing the likelihood that the p.Lys3196Glu variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735631	SCV000863769	uncertain significance	Breast and/or ovarian cancer	2003-02-11	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001269375	SCV001448723	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing