ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4262A>G (p.His1421Arg) (rs80357079)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203640 SCV000076520 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1421 of the BRCA1 protein (p.His1421Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 55157). 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 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.
GeneDx RCV000766583 SCV000210172 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4262A>G at the cDNA level, p.His1421Arg (H1421R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Using alternate nomenclature this variant would be defined as BRCA1 4381A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 His1421Arg was not observed in large population cohorts (Lek 2016). This variant is located in a coiled-coil region within the SCD domain, as well as in a region known to interact with multiple other proteins (Narod 2004, Sy 2009, Clark 2012, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 His1421Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000164576 SCV000215234 likely benign Hereditary cancer-predisposing syndrome 2018-04-20 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048507 SCV000296351 uncertain significance not specified 2017-06-01 criteria provided, single submitter clinical testing
Color RCV000164576 SCV000683168 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing
Mendelics RCV000203640 SCV000839237 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048507 SCV001370711 uncertain significance not specified 2020-05-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4262A>G (p.His1421Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251434 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4262A>G has been reported in the literature in at least an individual affected with breast cancer (Diaz-Zabala_2018). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000083206 SCV000115280 uncertain significance Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083206 SCV000145045 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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