ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8723T>G (p.Val2908Gly) (rs28897753)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167857 SCV000073621 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131647 SCV000186674 likely benign Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Michigan Medical Genetics Laboratories,University of Michigan RCV000077449 SCV000196017 likely benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000045608 SCV000210673 likely benign not specified 2017-04-04 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.
Counsyl RCV000077449 SCV000220798 likely benign Breast-ovarian cancer, familial 2 2014-10-15 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001281731 SCV000600820 likely benign not provided 2020-06-30 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000131647 SCV000679727 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131647 SCV000683994 likely benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045608 SCV000918926 likely benign not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8723T>G (p.Val2908Gly) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/247044 control chromosomes at a frequency of 0.0000162, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in breast cancer patients without strong evidence for causality, such as cosegregation with disease. In support of a benign impact, the variant has been found to co-occur in at least two patients with different deleterious BRCA1 mutations (one listed in UMD - c.3018_3021delTTCA; one listed in BIC - p.Tyr1563X). Additionally, numerous and diverse functional assays, such as survival assay by MMC (mitomycin-C) sensitivity, homology directed repair, and centriole amplification assays, showed that this variant behaves like wild-type (Wu_2005 and Farrugia_2008). Furthermore, eight clinical diagnostic laboratories/reputable databases have classified this variant as likely benign in ClinVar. Taken together, the evidence for a benign outcome far exceeds all other evidence, thus the variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000045608 SCV001157037 likely benign not specified 2018-11-08 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646835 SCV001852810 likely 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) RCV000077449 SCV000109247 likely benign Breast-ovarian cancer, familial 2 2008-10-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077449 SCV000147444 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353401 SCV000592224 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Val2908Gly variant was identified in 2 of 1782 proband chromosomes (frequency: 0.0001) from individuals or families with breast/ovarian cancers (Konecny 2011, van Harssel 2010). In functional studies comparing mutant and wildtype forms of BRCA2 using assays of cellular survival and viability, homologous recombination repair, genome instability and centriole amplification, the variant was comparable to wildtype or demonstrated no impaired BRCA2 function (Wu 2005, Farrugia 2008). In a computational multifactorial model combining three independent measures (co-occurrence of variant with known deleterious mutations, personal and family history of cancer, and co-segregation with disease), the variant was found to be neutral (Easton 2007). Another computational method looking at probabilistic likelihood ratio of variant (whether missense variant impairs protein function), was inconclusive (Karchin 2008). The variant was also identified in dbSNP (ID: rs28897753) “With other allele”, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 2 of 33026 individuals from a population of European (Non-Finnish) individuals (frequency: 0.00003), Clinvitae database (classifications likely benign and conflicting interpretations of pathogenicity), Fanconi Anemia Mutation Database (LOVD) and ARUP Laboratories BRCA Mutations Database (classified as likely not pathogenic or of little clinical significance), the ClinVar database (classified as likely benign by Ambry Genetics, GeneDX, Counsyl, Invitae, and Sharing Clinical Reports Project(derived from Myriad reports); and classified as uncertain significance by BIC), the BIC database (8x with unknown clinical importance, classification pending). The p.Val2908 residue is conserved across mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. 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.

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