Submissions for variant NM_000059.4(BRCA2):c.2680G>A (p.Val894Ile)

gnomAD frequency: 0.00011  dbSNP: rs28897715

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077283	SCV000244431	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 = 0.00000836
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084002	SCV000072050	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000160217	SCV000210580	likely benign	not specified	2017-11-08	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	RCV000162506	SCV000212896	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.
Counsyl	RCV000077283	SCV000220313	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-05-13	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588499	SCV000694617	benign	not provided	2016-01-08	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077283	SCV000743275	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	RCV000077283	SCV000744428	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162506	SCV000902686	benign	Hereditary cancer-predisposing syndrome	2016-04-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588499	SCV001472521	likely benign	not provided	2019-12-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162506	SCV002535515	likely benign	Hereditary cancer-predisposing syndrome	2021-09-10	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149671	SCV003838819	likely benign	Breast and/or ovarian cancer	2021-08-17	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160217	SCV004027411	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077283	SCV000109080	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-11-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077283	SCV000146087	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000077283	SCV000301445	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	RCV001353397	SCV000591816	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val894Ile variant was identified in 2 of 934 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer (Jarhelle 2016, van der Hout 2006). The variant was also identified in dbSNP (ID: rs28897715) as “with likely benign allele”, Clinvitae database (3x as “benign” and 1x as “likely benign”), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database (as not pathogenic), the ClinVar database (5x as “benign”, 1x as “likely benign”, and 1x as “uncertain significance”), the BIC database (17x with unknown clinical importance), and UMD (10x with a “likely neutral” classification. In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (p.Ser552ProfsX6), increasing the likelihood that the p.Val894Ile variant does not have clinical significance. This variant was also identified in the NHLBI GO Exome Sequencing Project in 4 of 8596 European American alleles and in 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 5 of 120344 chromosomes (freq. 4.16x10-5) in the following populations: African in 1 of 10124 chromosomes (freq. 9.88X10-5), and European (Non-Finnish) in 4 of 66318 chromosomes (freq. 6.03X10-5), but was not seen in East Asian, Finnish, Latino, and South Asian populations, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. In silico studies have classified the variant as benign: odds in favour of neutrality 2440 (Easton 2007), probability of being deleterious 8.36×10−6 (Lindor 2012), and as a variant of unknown significance (Guidugli 2013). The p.Val894 residue is not conserved in mammals and the variant amino acid Isoleucine is present in dogs, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000588499	SCV000778654	likely benign	not provided	2017-10-09	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000160217	SCV001905917	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000160217	SCV001951257	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000160217	SCV002036905	benign	not specified		no assertion criteria provided	clinical testing