ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3916G>A (p.Val1306Ile)

gnomAD frequency: 0.00002  dbSNP: rs80358636
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Total submissions: 16
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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) RCV000031447 SCV000244443 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 = 0.00000685
Invitae RCV000203660 SCV000072322 benign Hereditary breast ovarian cancer syndrome 2021-12-11 criteria provided, single submitter clinical testing
GeneDx RCV001200360 SCV000210599 likely benign not provided 2020-05-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 21990134, 22476429, 24323938, 20104584)
Ambry Genetics RCV000162737 SCV000213208 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000203660 SCV000257609 uncertain significance Hereditary breast ovarian cancer syndrome 2015-04-12 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000203660 SCV000890966 likely benign Hereditary breast ovarian cancer syndrome 2021-08-26 criteria provided, single submitter clinical testing The BRCA2 c.3916G>A (p.Val1306Ile) missense change has a maximum subpopulation frequency of 0.0041% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32912408-G-A). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/13-32907401-G-C). It has also been reported in an individual with breast cancer (PMID: 20104584). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS2_supporting, BP4.
Color Diagnostics, LLC DBA Color Health RCV000162737 SCV000902887 benign Hereditary cancer-predisposing syndrome 2015-08-11 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001200360 SCV001371296 likely benign not provided 2020-04-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044309 SCV001469683 benign not specified 2019-10-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044309 SCV001983741 benign not specified 2021-09-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3916G>A (p.Val1306Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 209536 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3916G>A has been reported in the literature in individuals undergoing testing for hereditary breast and/or ovarian cancer but has been classified as unequivocally neutral based on multifactorial probability models that employed several key parameters, namely co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees (example, Easton_2007, Lindor_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. No experimental evidence demonstrating an impact on protein function were ascertained within the context of this evaluation, although this variant has been included among the neutrality controls in validation panels reviewing functional assays for analysis of VUS in BRCA2 (example Guidugli_2012). Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments but a predominant consensus as benign (to include the expert panel)/likely benign (n=6). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory,University of Chicago RCV000044309 SCV002071938 likely benign not specified 2021-10-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001200360 SCV002506233 likely benign not provided 2022-01-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000162737 SCV002533835 likely benign Hereditary cancer-predisposing syndrome 2022-03-16 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031447 SCV000054052 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2009-10-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031447 SCV000146333 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000044309 SCV002550328 benign not specified 2021-10-05 no assertion criteria provided clinical testing

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