Submissions for variant NM_000059.4(BRCA2):c.6323G>A (p.Arg2108His)

gnomAD frequency: 0.00260  dbSNP: rs35029074

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031619	SCV000244465	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 = 0.000000000000372
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044912	SCV000072925	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000031619	SCV000154045	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000168589	SCV000167379	benign	not specified	2013-12-23	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.
CSER _CC_NCGL, University of Washington	RCV000148434	SCV000190133	likely benign	Breast neoplasm	2014-06-01	criteria provided, single submitter	research
Ambry Genetics	RCV000162540	SCV000212942	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768601	SCV000219377	benign	Breast and/or ovarian cancer	2016-01-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000168589	SCV000225177	benign	not specified	2014-12-11	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031619	SCV000267794	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000290378	SCV000383738	likely benign	Fanconi anemia complementation group D1	2018-03-08	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000031619	SCV000383739	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-08	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168589	SCV000538467	benign	not specified	2016-05-11	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: ClinVar: Ben by expert panel
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000168589	SCV000586967	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168589	SCV000593722	benign	not specified	2018-08-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656612	SCV000602844	benign	not provided	2022-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162540	SCV000683774	benign	Hereditary cancer-predisposing syndrome	2015-03-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031619	SCV000743319	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031619	SCV000744487	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000031619	SCV001139145	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044912	SCV002025797	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044912	SCV002515133	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162540	SCV002536224	benign	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168589	SCV002551814	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656612	SCV002585443	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031619	SCV004016895	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000656612	SCV005236063	benign	not provided		criteria provided, single submitter	not provided
Sharing Clinical Reports Project (SCRP)	RCV000031619	SCV000054226	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031619	SCV000146825	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000031619	SCV000189896	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000168589	SCV000592043	benign	not specified		no assertion criteria provided	clinical testing	The p.Arg2108His variant has been reported in the literature in 14/19788 proband chromosomes in individuals with breast cancer, prostate cancer and cutaneous melanoma (Borg_2010, Caux-Moncoutier_2009, Caux-Moncoutier_2011,de Sanjose_2003, Diez_2003, Gomez-Garcia_2005, Kote-Jarai_2011, Lindor_2012, Monnerat_2007). It was not, however, found in any of the 100 control chromosomes tested. It is listed in the dbSNP database as coming from a "clinical source" (ID#:rs35029074) with a global minor allele frequency (MAF) of 0.001 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. The variant was also identified in the LOVD (X2), UMD (X68), Exome server, BIC (X127) and BOCs databases; in the latter database it was classified as a benign variant with an ACMG 5 designation. In the UMD database, this variant has been identified in nine individuals with a second pathogenic in BRCA1 [c.6078dup (p.Arg2027LysfsX22), c.1440_1441delCA (p.Ile481SerfsX32)] and BRCA2 [c.IVS16+6T>C (c.4986+6T>C), c.442_4357del (p.Glu149TyrfsX2), c.4485_4675del (p.Ser1496GlyfsX14), c.2679_2682delGAAA (p.Lys893AsnfsX106)], thereby increasing the likelihood that this variant does not have clinical significance. This residue is not conserved in mammals and the variant amino acid Histidine (His) is present in chicken at this position, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen, SIFT, AlignGVGD) do not predict any effect on the protein function, however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant is classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031619	SCV000733280	benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656612	SCV000778697	benign	not provided	2017-02-20	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162540	SCV000787939	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528143	SCV000805740	likely benign	BRCA2-related disorder	2019-05-23	no assertion criteria provided	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).
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168589	SCV001906336	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168589	SCV001951816	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000168589	SCV002035795	benign	not specified		no assertion criteria provided	clinical testing