Submissions for variant NM_000059.4(BRCA2):c.6100C>T (p.Arg2034Cys)

gnomAD frequency: 0.00268  dbSNP: rs1799954

Total submissions: 47

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113532	SCV000244462	benign	Breast-ovarian cancer, familial, susceptibility to, 2	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 = 0.00000571
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044844	SCV000072857	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113532	SCV000154068	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-02-06	criteria provided, single submitter	literature only
GeneDx	RCV000120331	SCV000167377	benign	not specified	2013-10-09	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113532	SCV000195996	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162509	SCV000212900	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: 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.
Eurofins Ntd Llc (ga)	RCV000120331	SCV000225165	benign	not specified	2014-08-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113532	SCV000383731	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-27	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044844	SCV000494335	benign	Hereditary breast ovarian cancer syndrome	2014-02-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034452	SCV000511453	benign	not provided	2016-06-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000461415	SCV000541060	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000113532	SCV000575742	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-09	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044844	SCV000576435	likely benign	Hereditary breast ovarian cancer syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120331	SCV000586965	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000120331	SCV000588107	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120331	SCV000593721	benign	not specified	2017-03-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034452	SCV000602767	benign	not provided	2023-10-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034452	SCV000608682	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS2
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113532	SCV000743316	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113532	SCV000744482	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120331	SCV000805734	benign	not specified	2016-09-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162509	SCV000910521	benign	Hereditary cancer-predisposing syndrome	2015-10-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000113532	SCV001139136	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000113532	SCV001429037	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-11-12	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034452	SCV002010343	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044844	SCV002025794	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044844	SCV002515129	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162509	SCV002536203	benign	Hereditary cancer-predisposing syndrome	2020-09-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120331	SCV002550359	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492326	SCV004240334	benign	Breast and/or ovarian cancer	2022-10-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113532	SCV004846699	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000120331	SCV005199801	benign	not specified	2022-05-27	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034452	SCV005236062	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034452	SCV000043219	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120331	SCV000084483	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113532	SCV000146768	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113532	SCV000189312	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-10	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000113532	SCV000189907	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000113532	SCV000301450	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120331	SCV000592030	benign	not specified		no assertion criteria provided	clinical testing	The p.Arg2034Cys variant has been identified in 42 out of 7668 proband chromosomes (frequency 0.005) in individuals with unilateral and contralateral breast cancer and familial breast and ovarian cancer phenotype, and also found in 39 out of 3186 control chromosomes (frequency 0.012) included in these studies (Johnson 2007, Schoumacher 2001, Wagner 1999, Capanu 2011, Borg 2010, Hondow 2011, Salazar 2006, Diez 2003, Simard 2006, Miramar 2008, Beristain 2007). It is also listed in dbSNP database coming from a “clinical source” (ID#: rs1799954) with a “global minor allele frequency of 0.001 (1000 genomes), therefore increasing the likelihood that this variant is benign. The p.Arg2034 is not conserved in mammals but was conserved in birds, reptiles, frogs and fish, therefore decreasing the likelihood that this variant has functional significance. Furthermore, the computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In the UMD database, this variant has been identified in 22 (out of 137) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 or BRCA2 mutation was also detected, further suggesting that this is a benign variant. In summary, based on the above information, this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113532	SCV000733278	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034452	SCV000778695	likely benign	not provided	2017-02-21	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162509	SCV000788118	likely benign	Hereditary cancer-predisposing syndrome	2017-11-10	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000120331	SCV001799136	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120331	SCV001906369	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120331	SCV001955578	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000113532	SCV004243702	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing