ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4255G>C (p.Glu1419Gln) (rs80357309)

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Total submissions: 9
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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) RCV000112305 SCV000244357 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 = 0.000152
Invitae RCV000048503 SCV000076516 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-07-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1419 of the BRCA1 protein (p.Glu1419Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with personal/family history of breast and/or ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 55154). Multifactorial likelihood analysis based on genetic data including personal/family history, co-occurrence, and co-segregation predicts that this variant is neutral or of no clinical significance (PMID: 17924331, 21990134). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is predicted to preserve protein function and to be neutral by genetic evidence-based likelihood analysis. This variant is not expected to cause disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000162984 SCV000213472 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
GeneDx RCV000235288 SCV000293656 likely benign not specified 2017-07-07 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235288 SCV000591501 likely benign not specified 2012-11-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588065 SCV000699125 likely benign not provided 2017-03-07 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4255G>C (p.Glu1419Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121396 control chromosomes. However, multiple publications cite the variant with a classification of "likely neutral." In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "benign/likely benign/uncertain significance." In addition, a poster abstract (IUBMB 2015) cites a functional study that showed the variant to act comparable to wild type functions for transcriptional activation ability and PALB2 interaction. One recent functional study (Woods_2016) showed preserved transcriptional activity and no deleterious effects on the BRCA1-PALB2 protein-protein interaction in the presence of this variant. Taken together, this variant is classified as likely benign.
Color RCV000162984 SCV000903861 benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112305 SCV000145042 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735479 SCV000863616 likely benign Breast and/or ovarian cancer 2012-08-27 no assertion criteria provided clinical testing

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