ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4255G>C (p.Glu1419Gln) (rs80357309)

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Total submissions: 10
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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 RCV001078624 SCV000076516 likely benign Hereditary breast and ovarian cancer syndrome 2020-07-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162984 SCV000213472 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.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000162984 SCV000903861 benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588065 SCV001133579 likely benign not provided 2018-12-03 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000112305 SCV000591501 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The p.Glu1419Gln variant has been identified in 2/114310 proband chromosomes of individuals with breast cancer and/or ovarian cancer; although, no control chromosomes were tested to establish the variant's frequency in the general population (Caux-Moncoutier 2011, Judkins 2005a, Lindor 2011, Millot 2012). The variant is listed in dbSNP database (ID#:rs80357309) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Glu1419 residue is conserved in mammals, but computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, this variant is listed in the BIC (x1) database, as well as in the UMD mutation database to co-occur with a pathogenic mutation in BRCA2 c.3744_3747delTGAG (p.Ser1248ArgfsX10), increasing the likelihood that p.Glu1419Gln is benign. In summary, based on the above information, the p.Arg3370Arg variant is classified as predicted benign.
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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