Submissions for variant NM_000059.4(BRCA2):c.6347A>G (p.His2116Arg)

gnomAD frequency: 0.00396  dbSNP: rs55953736

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113577	SCV000321286	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-28	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.025 (African), derived from 1000 genomes (2013-05-02).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167845	SCV000072932	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000113577	SCV000154071	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-02-18	criteria provided, single submitter	literature only
Ambry Genetics	RCV000131142	SCV000186080	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000113577	SCV000195997	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120324	SCV000225190	benign	not specified	2015-07-08	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000131142	SCV000267021	likely benign	Hereditary cancer-predisposing syndrome	2016-01-04	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000167845	SCV000296856	benign	Hereditary breast ovarian cancer syndrome	2015-10-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000113577	SCV000383742	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-06-20	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	RCV000395640	SCV000383743	likely benign	Fanconi anemia complementation group D1	2018-06-20	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167845	SCV000494337	benign	Hereditary breast ovarian cancer syndrome	2014-03-12	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034456	SCV000511251	likely benign	not provided	2016-09-20	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Fulgent Genetics, Fulgent Genetics	RCV000113577	SCV000575757	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120324	SCV000593723	benign	not specified	2017-10-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034456	SCV000602846	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131142	SCV000683776	benign	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113577	SCV000743320	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-06-15	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113577	SCV000744488	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-31	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131142	SCV000747814	likely benign	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120324	SCV000805742	benign	not specified	2016-12-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131142	SCV002536230	benign	Hereditary cancer-predisposing syndrome	2020-10-29	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034456	SCV002545111	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS1, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000148423	SCV003838167	benign	Breast and/or ovarian cancer	2022-03-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000113577	SCV004016878	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120324	SCV004027459	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034456	SCV005236064	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034456	SCV000043223	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
ITMI	RCV000120324	SCV000084476	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113577	SCV000146832	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148423	SCV000190122	likely benign	Breast and/or ovarian cancer	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120324	SCV000592045	benign	not specified		no assertion criteria provided	clinical testing	The p.His2116Arg variant has been reported in the literature in 13/19710 proband chromosomes of individuals with breast cancer and prostate cancer; it was not detected in the 122 control chromosomes tested (Berg_2012_22995991, Borg_2010_20104584, Carvalho_2007_17308087, Caux-Moncoutier_2011_21120943, Haffty_2006_15983021, Johnston_2012_22703879, Kote-Jarai_2011_21952622, Lee_2008_18284688, Tazzite_2012_22425665), however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. It has also been reported in the HGMD, BIC(x88 as not clinically important), Exome Variant Server and BOCs databases. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs55953736) with a global minor allele frequency (MAF) of 0.002 (1000 Genomes) and was also identified by the EVS project as a low frequency variant. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. It was identified 18x in the UMD database, 6x as co-occuring with a second pathogenic variant, increasing the likelihood this variant does not have clinical significance. Furthermore, Myriad genetics classifies this variant as a polymorphism (personal communication). In summary, this variant meets our criteria to be classified as benign.
True Health Diagnostics	RCV000131142	SCV000787940	likely benign	Hereditary cancer-predisposing syndrome	2018-01-24	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034456	SCV001800811	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120324	SCV001906353	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120324	SCV001955584	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167845	SCV001977040	benign	Hereditary breast ovarian cancer syndrome	2021-09-27	no assertion criteria provided	clinical testing