ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1865C>T (p.Ala622Val) (rs56039126)

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Total submissions: 13
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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) RCV000111700 SCV000244309 benign Breast-ovarian cancer, familial 1 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 = 0.0000212
Invitae RCV000167782 SCV000075623 benign not provided 2019-02-06 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148408 SCV000190107 uncertain significance Neoplasm of the breast 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000047610 SCV000209932 likely benign not specified 2017-07-24 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 RCV000162564 SCV000212977 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000111700 SCV000267694 likely benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768617 SCV000324824 uncertain significance Breast and/or ovarian cancer 2015-08-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000047610 SCV000538450 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multple papers describe as VUS; ClinVar: 2 B/LB, 3 VUS
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047610 SCV000591354 uncertain significance not specified 2015-08-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000047610 SCV000698893 benign not specified 2019-03-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1865C>T (p.Ala622Val) 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 6.5e-05 in 276900 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (6.5e-05 vs 0.001), allowing no conclusion about variant significance. c.1865C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, however, with limited information (ie, lack of co-occurrence and/or cosegregation data)(Tikhomirova_2007, Wagner_1998, Moghadasi_2013, Anczukow_2008, Borg_2010, Judkins_2005, Lee_2008, Palma_2008, Wong-Brown_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other likely pathogenic/pathogenic variants have been reported (BRCA2 c.5722_5723delCT, p.Leu1908Argfs; BRCA2 c.658_659delGT, p.Val220Ilefs; BRCA2 c.6275_6276delTT, p.Leu2092Profs; BRIP1 c.440dupA, p.Tyr147X), providing supporting evidence for a benign role. Variant was functionally assessed to have no impact on splicing (Anczukow_2008). Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant four times as likely benign/benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Color RCV000162564 SCV000902725 benign Hereditary cancer-predisposing syndrome 2016-03-08 criteria provided, single submitter clinical testing
Mendelics RCV000111700 SCV001140593 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111700 SCV000144203 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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