ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.398G>A (p.Arg133His) (rs80357357)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128888 SCV000172747 likely benign Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing Other data supporting benign classification
GeneDx RCV000443460 SCV000517330 likely benign not specified 2016-10-21 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.
Color Health, Inc RCV000128888 SCV000909412 likely benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000443460 SCV000916766 uncertain significance not specified 2018-06-18 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.398G>A (p.Arg133His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246244 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.398G>A has been reported in the literature, without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A functional study reporting two DNA repair assays showed the variant to have proficient activity (Towler_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
Mendelics RCV000031138 SCV001140637 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001479032 SCV001683322 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031138 SCV000053737 likely benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031138 SCV000145279 uncertain significance Breast-ovarian cancer, familial 1 1999-06-22 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353645 SCV000591263 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Arg133His variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC databases. It is listed in the dbSNP database (rs#80357357) but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The p.Arg133 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg133His variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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