Submissions for variant NM_007294.4(BRCA1):c.591C>T (p.Cys197=)

gnomAD frequency: 0.00117  dbSNP: rs1799965

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566896	SCV004101431	benign	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.591C>T variant in BRCA1 is a synonymous variant (p.Cys197=). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.001402 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates no impact on splicing or an increase of in-frame naturally occurring splice isoforms with production of wildtype transcripts (PMIDs: 19892845, 22505045, 24607278, 23239986), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.33E-16 (based on Pathology LR=1.33E-16), below the threshold for very strong benign evidence (LR <0.00285) (BP5_Very strong met; ENIGMA internal contributor). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP7_Strong (RNA), BP5_Very strong).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049065	SCV000077078	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000112746	SCV000154027	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-03-17	criteria provided, single submitter	literature only
GeneDx	RCV000168484	SCV000167232	benign	not specified	2013-11-01	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	RCV000131013	SCV000185939	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: 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112746	SCV000195885	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735462	SCV000219193	benign	Breast and/or ovarian cancer	2017-06-12	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000168484	SCV000232716	benign	not specified	2015-05-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168484	SCV000246805	benign	not specified	2019-04-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000415785	SCV000493690	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BS1, BS2
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168484	SCV000538440	likely benign	not specified	2016-03-29	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: ExAC: 0.6% (45/6615) Finnish chromosomes; ClinVar: 7 labs classify as B/LB
Color Diagnostics, LLC DBA Color Health	RCV000131013	SCV000683339	likely benign	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000415785	SCV000885077	benign	not provided	2023-10-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000112746	SCV001140629	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112746	SCV001284089	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000112746	SCV001440661	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000049065	SCV002026018	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000049065	SCV002515143	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131013	SCV002537876	benign	Hereditary cancer-predisposing syndrome	2020-07-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168484	SCV002551049	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112746	SCV004016769	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000049065	SCV005045452	benign	Hereditary breast ovarian cancer syndrome	2024-03-12	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112746	SCV000145632	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112746	SCV000189349	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-15	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000168484	SCV000587065	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353617	SCV000591288	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Cys197Cys variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It has been previously identified by our laboratory and has been reported as a benign variant. It has also been reported in the literature in 35 out of 5616 proband chromosomes of individuals from families with hereditary breast and ovarian cancers, and was classified as a variant of benign significance or as a polymorphism; it was also found in 6 out of 1964 control chromosomes (Bergthorsson_2001_11389159, Diez_2003_12955716, Dosil_2010_19892845, Ladopoulou_2002_10980541, McKean-Cowdin_2005_15726418, Stegel_2011_21232165, Takahashi_1995_7606717). In addition, this variant is listed in the UMD mutation database as a neutral variant and observed to co-occur with other BRCA1 pathogenic mutations: c.4327C>T (p.Arg1443X), c.5123C>A (p.Ala1708Glu), c.68_69delAG (p.Glu23ValfsX17), c.IVS6-1G>A (c.302-1G>A), increasing the likelihood that the p.Cys179Cysvariant does not have any clinical significance. This variant is listed in the dbSNP database as coming from a "clinical source" (ID#:rs1799965) but no frequency information was provided, and so the prevalence of this variant in the population is not known. In addition, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, the p.Cys197Cys variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000112746	SCV000733667	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000415785	SCV000778775	likely benign	not provided	2017-05-31	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131013	SCV000787912	likely benign	Hereditary cancer-predisposing syndrome	2017-07-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758634	SCV000806979	benign	BRCA1-related disorder	2024-08-19	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735462	SCV000863599	benign	Breast and/or ovarian cancer	2012-06-08	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000168484	SCV001800141	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168484	SCV001906048	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000168484	SCV001927142	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168484	SCV001952158	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000168484	SCV001967352	benign	not specified		no assertion criteria provided	clinical testing