ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4245A>G (p.Glu1415=) (rs41293453)

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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) RCV000112303 SCV000578431 likely benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae RCV001080470 SCV000076512 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163656 SCV000214226 likely benign Hereditary cancer-predisposing syndrome 2014-11-20 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
GeneDx RCV000483384 SCV000564741 likely benign not specified 2017-12-06 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000483384 SCV000699124 likely benign not specified 2019-07-25 criteria provided, single submitter clinical testing
Counsyl RCV000112303 SCV000785995 likely benign Breast-ovarian cancer, familial 1 2018-01-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586731 SCV000888914 likely benign not provided 2019-12-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163656 SCV000902936 likely benign Hereditary cancer-predisposing syndrome 2015-08-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112303 SCV001283850 uncertain significance Breast-ovarian cancer, familial 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112303 SCV000145039 uncertain significance Breast-ovarian cancer, familial 1 2000-01-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353593 SCV000591500 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Glu1415Glu variant was identified in 1 of 820 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer, and was not identified in 200 control chromosomes from healthy individuals; the authors call this variant a polymorphism (Diez 2003).The variant was also identified in dbSNP (ID: rs41293453) “With Uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server), the ClinVar database (classified as an uncertain significance variant by the BIC), the BIC database (3X with unknown clinical importance), and UMD (1X as an unclassified variant).The variant was identified by the Exome Variant Server project in 3 of 13006 European American and African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Glu1415Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. Thus, this variant is classified as predicted benign.

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