ClinVar Miner

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

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Total submissions: 11
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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 2020-10-30 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 observed in individual(s) with breast cancer (PMID: 30400234). 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 2020-09-15 criteria provided, single submitter clinical testing Observed in individuals with breast cancer (Diaz-Zabala 2018); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also know as 4381A>G; This variant is associated with the following publications: (PMID: 30400234, 23704879, 31112341, 31131967)
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 Health, Inc 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048507 SCV001370711 uncertain significance not specified 2021-06-13 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287848 SCV001474585 uncertain significance none provided 2019-09-30 criteria provided, single submitter clinical testing The BRCA1 c.4262A>G; p.His1421Arg variant (rs80357079), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 55157). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The histidine at codon 1421 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Other amino acid substitutions at this codon (p.His1421Leu, p.His1421Tyr) have been reported in individuals with a personal or family history of breast and/or ovarian cancer, although their clinical significance was not demonstrated (Akbari 2011, Vogel 2007). Given the lack of clinical and functional data, the significance of the p.His1421Arg variant is uncertain at this time. References: Akbari MR et al. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. J Med Genet. 2011 Nov;48(11):783-6 Vogel KJ et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol. 2007 Oct 10;25(29):4635-41.
Research and Development, ARUP Laboratories RCV001662272 SCV001878365 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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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