ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2680G>A (p.Val894Ile) (rs28897715)

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Total submissions: 18
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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 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
Invitae RCV001084002 SCV000072050 benign Hereditary breast and ovarian cancer syndrome 2020-11-23 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: 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 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 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 2 2015-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162506 SCV000902686 benign Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286004 SCV001472521 likely benign none provided 2019-12-13 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646087 SCV001854728 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077283 SCV000109080 benign Breast-ovarian cancer, familial 2 2012-11-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077283 SCV000146087 uncertain significance Breast-ovarian cancer, familial 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 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
Human Genetics - Radboudumc,Radboudumc RCV000160217 SCV001951257 benign not specified no assertion criteria provided clinical testing

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