ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2936G>A (p.Arg979His) (rs80356985)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048020 SCV000076033 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 979 of the BRCA1 protein (p.Arg979His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs80356985, ExAC 0.006%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 54728). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000216248 SCV000276670 likely benign Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
GeneDx RCV000590371 SCV000292714 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2936G>A at the cDNA level, p.Arg979His (R979H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). Using alternate nomenclature, this variant would be defined as BRCA1 3055G>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Arg979His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and the RAD51 binding domain (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Arg979His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590371 SCV000698989 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The c.2936G>A (p.Arg979His) in BRCA1 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain. The variant is present in control dataset of ExAC at a low frequency of 0.000008 (1/121054chrs tested) which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.001). This variant has not, to our knowledge, been reported in affected individuals via published reports, but is cited as VUS/Likely Benign by reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS until more information becomes available.
Color RCV000216248 SCV000905496 likely benign Hereditary cancer-predisposing syndrome 2015-09-21 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111970 SCV000144589 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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