ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3839A>T (p.Asp1280Val) (rs56337919)

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Total submissions: 10
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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) RCV000077315 SCV000244442 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 = 0.0000286
Invitae RCV001080923 SCV000072291 benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000044278 SCV000210597 likely benign not specified 2018-01-12 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 RCV000162783 SCV000213261 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 RCV000077315 SCV000487915 benign Breast-ovarian cancer, familial 2 2015-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044278 SCV000694722 benign not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3839A>T (p.Asp1280Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 212168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3839A>T has been reported in the literature in sequencing studies of individuals with high risk breast cancer as well as in an unaffected individual (Lu_2012, Carney_2010) in addition to sequencing studies of patients undergoing cancer screening for varied indications (example, Easton_2007, DeLeeneer_2008, Seymour_2008, Hartman_2001, Machackova_2019). These reports do not provide unequivocal conclusions regarding the association of this variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.66dupA, p.Glu23fsX18), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign (n=4)/likely benign(n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. We have not identified any evidence supporting an actionable outcome in over 5 years since its initial classification by our laboratory. Based on the evidence outlined above, and the predominant consensus in the field, the variant was classified as benign.
PreventionGenetics,PreventionGenetics RCV000587147 SCV000805700 likely benign not provided 2017-06-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162783 SCV000902727 benign Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077315 SCV000109112 benign Breast-ovarian cancer, familial 2 2009-10-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077315 SCV000146306 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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