ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4094G>A (p.Cys1365Tyr) (rs80358657)

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Total submissions: 11
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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) RCV000031459 SCV000244446 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 = 0.000136
Invitae RCV000044346 SCV000072359 benign Hereditary breast and ovarian cancer syndrome 2020-11-20 criteria provided, single submitter clinical testing
GeneDx RCV001535398 SCV000210602 likely benign not provided 2021-03-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32659497, 29958926, 29309945, 28767289, 25479140, 27997549, 23633455, 22711857, 27376475, 21990134, 17924331, 19491284, 10923033, 24323938)
Ambry Genetics RCV000162841 SCV000213328 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 RCV000031459 SCV000784931 benign Breast-ovarian cancer, familial 2 2017-02-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770725 SCV000902204 uncertain significance Breast and/or ovarian cancer 2016-07-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162841 SCV000910846 benign Hereditary cancer-predisposing syndrome 2015-12-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160222 SCV000919002 likely benign not specified 2018-09-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4094G>A (p.Cys1365Tyr) results in a non-conservative amino acid change located in the BRCA2 repeat region, between the repeats BRC2 and BRC3 (IPR002093), i.e. not affecting a known functional domain. 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 3.3e-05 in 244272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4094G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer or other tumor phenotypes, however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with other pathogenic variants have been reported (with BRCA1 c.1175_1214del, p.Leu392_Ser405?fs in the BIC database), providing supporting evidence for a benign role. The variant was predicted to be neutral based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations (Lindor 2012) and using a model based co-occurrence in trans with a deleterious mutation, personal and family history of cancer, and analysis of co-segregation with disease (Easton 2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as Likely Benign.
Research and Development, ARUP Laboratories RCV001642325 SCV001854788 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) RCV000031459 SCV000054064 benign Breast-ovarian cancer, familial 2 2009-06-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031459 SCV000146373 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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