Submissions for variant NM_000059.4(BRCA2):c.1275A>G (p.Glu425=)

gnomAD frequency: 0.00324  dbSNP: rs34355306

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)	RCV000112901	SCV000245003	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01016 (African), derived from 1000 genomes (2012-04-30).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084122	SCV000071784	benign	Hereditary breast ovarian cancer syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000112901	SCV000154037	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000173633	SCV000167330	benign	not specified	2013-10-29	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	RCV000112901	SCV000195958	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162729	SCV000213195	benign	Hereditary cancer-predisposing syndrome	2015-11-10	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)	RCV000173633	SCV000224763	benign	not specified	2014-12-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000458106	SCV000541051	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000173633	SCV000593740	benign	not specified	2017-06-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656586	SCV000602880	benign	not provided	2024-05-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162729	SCV000683412	benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000173633	SCV000805651	benign	not specified	2017-07-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001115061	SCV001273001	benign	Fanconi anemia complementation group D1	2019-05-06	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000112901	SCV001273002	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-06	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001084122	SCV002026067	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001084122	SCV002515248	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001084122	SCV004014888	benign	Hereditary breast ovarian cancer syndrome	2023-02-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492344	SCV004240290	benign	Breast and/or ovarian cancer	2023-06-09	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000656586	SCV005236036	benign	not provided		criteria provided, single submitter	not provided
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112901	SCV000145844	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353996	SCV000591734	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Glu425Glu variant was identified in 29 of 2532 proband chromosomes (frequency: 0.011) from individuals or families with breast cancer, and was not identified in 334 control chromosomes from healthy individuals (Fackenthal 2012, Han 2006, Kawahara 2004, Toh 2008). The variant was also identified in dbSNP (ID: rs34355306) as “With Likely benign allele”, Clinvitae database (classified as benign by ClinVar and Invitae, as likely benign by ClinVar), the ClinVar database (classified as benign by ENIGMA, MMGLUM, Invitae, GeneDx, Emory genetics, BIC, as likely benign by Counsyl and Ambry genetics), the BIC database (2x with no clinical importance), UMD (70x with a “unclassified variant” classification) and Fanconi Anemia Mutation Database (LOVD). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1: c.4986+6T>C, c.5468-2A>G and BRCA2: c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Glu425Glu variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 33 of 5000 chromosomes (frequency: 0.007), the NHLBI GO Exome Sequencing Project in 43 of 4400 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 161 (2 homozygous) of 120508 chromosomes (freq. 0.001) in the following populations: African in 138 of 9866 chromosomes (freq. 0.01), East Asian in 20 of 8642 chromosomes (freq. 0.002), Latino in 3 of 11540 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant. The p.Glu425Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656586	SCV000778643	likely benign	not provided	2017-10-09	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162729	SCV000787918	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000173633	SCV001905780	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000173633	SCV001957559	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656586	SCV001974430	likely benign	not provided		no assertion criteria provided	clinical testing