Submissions for variant NM_000059.4(BRCA2):c.2350A>G (p.Met784Val)

gnomAD frequency: 0.00018  dbSNP: rs11571653

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113034	SCV000245024	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 0.02797 (Asian), derived from 1000 genomes (2012-04-30).
Invitae	RCV000195303	SCV000071990	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000120314	SCV000167342	benign	not specified	2013-10-03	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	RCV000131146	SCV000186086	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: 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.
Counsyl	RCV000113034	SCV000220807	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-16	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000270154	SCV000383649	likely benign	Fanconi anemia complementation group D1	2017-04-27	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). 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	RCV000113034	SCV000383650	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	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.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000412901	SCV000492493	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120314	SCV000538471	likely benign	not specified	2016-03-28	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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034435	SCV000883509	benign	not provided	2017-10-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131146	SCV000910571	benign	Hereditary cancer-predisposing syndrome	2015-10-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000113034	SCV001139028	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120314	SCV002068988	likely benign	not specified	2021-10-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131146	SCV002535493	benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153320	SCV003843357	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034435	SCV000043203	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120314	SCV000084466	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113034	SCV000146033	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113034	SCV000189299	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353474	SCV000591802	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Met784Val variant has been reported in the literature in 160/11460 proband chromosomes of individuals with HBOC and sporadic breast cancer. It was also found in 35/5936 control chromosomes tested, increasing the likelihood this variant does not have clinical significance (Spearman 2008, Wagner 1999, Capanu 2011, Freedman_2004, Ishitobi_2003, Johnston_2012, Krupa_2009, Seo_2004, Han_2006). The variant has also been reported in the UMD (x1), LOVD (x2), BIC (x47), and BOCs databases. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs11571653) with a MAF score of 0.007 (1000 Genomes). Of particular interest are the findings that this variant is considered a polymorphism in the Japanese population, and that of the 168 chromosomes tested in the HapMap Japanese cohort, the variant was found in almost 20 chromosomes (allele frequency of 0.107). The p.Met784 residue is not conserved in mammals, and the variant amino acid Valine (Val) is present in the dog, rat and opossum at this position, increasing the likelihood that an alteration to this residue may not have functional significance. The identification of this variant in the presence of a second pathogenic variant increases the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is classified as Benign.
True Health Diagnostics	RCV000131146	SCV000787924	likely benign	Hereditary cancer-predisposing syndrome	2018-02-15	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034435	SCV002036638	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034435	SCV002037971	likely benign	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250501	SCV002520942	likely benign	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000113034	SCV004244245	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing