Submissions for variant NM_007294.4(BRCA1):c.1486C>T (p.Arg496Cys)

gnomAD frequency: 0.00023  dbSNP: rs28897676

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111629	SCV000244303	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000891
Invitae	RCV001084143	SCV000075506	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148399	SCV000190098	uncertain significance	Breast and/or ovarian cancer	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000047493	SCV000209927	benign	not specified	2015-07-28	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	RCV000162551	SCV000212961	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000047493	SCV000538439	likely benign	not specified	2017-02-03	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: Classified in ClinVar with 3 stars as Benign by ENIGMA (expert panel), Invitae, GeneDx, Ambry and as VUS by CSER and BIC. It has a max MAF of 0.026% in ExAC (3 Latino alleles). The AA is not conserved and only mammals have this region, 6 of which have a Cys at this position.
Genetic Services Laboratory, University of Chicago	RCV000047493	SCV000593661	likely benign	not specified	2016-08-02	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162551	SCV000679701	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162551	SCV000682964	likely benign	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003891451	SCV000806897	likely benign	BRCA1-related condition	2019-11-05	criteria provided, single submitter	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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000148399	SCV000902231	likely benign	Breast and/or ovarian cancer	2021-07-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000111629	SCV001140602	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000047493	SCV001159073	benign	not specified	2018-10-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162551	SCV002538033	likely benign	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000047493	SCV002760944	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482926	SCV002796085	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-11-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656641	SCV004041996	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BS3:Moderate, BS4
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111629	SCV000144109	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000047493	SCV000587141	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353852	SCV000591335	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Arg496Cys variant is identified in the literature in 6 out of 7356 proband chromosomes (frequency 0.001) with breast and ovarian cancers, however a limited number of control chromosomes were analyzed (0 out of 700, frequency=0), and so the frequency of this variant in the general population could not adequately be assessesed (Infante 2006, Chenevix-Trench 2006, Van-Hassel 2010, Borg 2010, German consortium 2002, Arnold 2002). It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897676) with an average heterozygosity of 0.000+/-0.015 from one population. The BIC database reports this variant 46X with unknown clinical importance. It is reported 52 times in the myriad database "in trans" and therefore likely to be neutral (Chenevix-Trench 2006). In the UMD database, this variant has been identified in 12 individuals with breast or ovarian cancers, and in 4 of these cases a second pathogenic BRCA1 or BRCA2 mutation was also detected, therefore increasing the likelihood this variant is benign. The p.Arg496 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, and other in silico analysis do not show any impact on the function (Lovelock 2007, Lindor 2011, Capanu 2011, Waddel 2008, Lee 2008, Mark_2005_15571721, Judkins_2005_16267036). Another variant at the same location, p.Arg496His, is also found 12 times in UMD database, with a second pathogenic variant co-occurring in 5 individuals with beast and ovarian cancer phenotype, decreasing the likelihood the p.Arg496Cys variant has clinical significance. In summary, based upon the above information, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656641	SCV000778768	likely benign	not provided	2017-03-30	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000148399	SCV000863586	uncertain significance	Breast and/or ovarian cancer	2001-10-10	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000047493	SCV001906131	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000047493	SCV001926834	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000047493	SCV001954549	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000047493	SCV001966239	benign	not specified		no assertion criteria provided	clinical testing