ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5572A>C (p.Ile1858Leu) (rs765656957)

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Total submissions: 8
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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) RCV000191157 SCV000244405 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 = 0.0000697
Ambry Genetics RCV000162994 SCV000213482 benign Hereditary cancer-predisposing syndrome 2014-11-18 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 RCV000191157 SCV000487900 benign Breast-ovarian cancer, familial 1 2015-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000445348 SCV000512323 likely benign not specified 2018-01-31 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.
Invitae RCV001085714 SCV000549368 benign Hereditary breast and ovarian cancer syndrome 2020-10-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162994 SCV000688643 likely benign Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588511 SCV000699274 likely benign not provided 2016-03-24 criteria provided, single submitter clinical testing Variant summary: The variant c.5572A>C affects a not conserved nucleotide, resulting in amino acid change from Ile to Leu. 4/4 in-silico tools predict this variant to be benign. This variant was found in 8/120940 control chromosomes including the large and broad populations of ExAC at a frequency of 0.0000661. It was only found in South Asian population; its allele frequency in South Asian cohort from ExAC is 0.0004 (7/16392 chromosomes). These frequencies do not exceed the maximal expected frequency of a pathogenic allele (0.0010005); however, it may still suggest that this variant is a rare polymorphism in the South Asians. In a study reported by Juwle et al 2012, this variant's frequency in 100 control chromosomes was 0.01 and the authors call the variant as a polymorphism. Despite the small sample size, selection of the controls is quite appropriate in the study, i.e. they used elderly control subjects. From a genetic analysis (employing 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), this variant was found to have high odds in favor of neutrality and a very low probability of being deleterious (Easton_2007, Lindor_2012). One clinical lab as well as reputable databases has classified this variant as benign. Taken together, this variant has currently been classified as Probable Normal Variant or Likely Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000445348 SCV000888953 benign not specified 2019-11-22 criteria provided, single submitter clinical testing

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