ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2597G>A (p.Arg866His) (rs80356911)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047893 SCV000075906 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 866 of the BRCA1 protein (p.Arg866His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs80356911, ExAC 0.01%). This variant has been reported in the literature in families with breast and/or ovarian cancer (PMID: 18273839, 25948282, 24504028). ClinVar contains an entry for this variant (Variation ID: 54613). 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 disruptive, 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.
Ambry Genetics RCV000130531 SCV000185400 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Michigan Medical Genetics Laboratories,University of Michigan RCV000077524 SCV000195908 uncertain significance Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000589478 SCV000566693 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2597G>A at the cDNA level, p.Arg866His (R866H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). Using alternate nomenclature, this variant has been previously published as BRCA1 2716G>A. This variant has been observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Anczukow 2008, Cunningham 2014, Kluska 2015) and was shown in an in vitro functional study to not have a significant effect on splicing (Anczukow 2008). BRCA1 Arg866His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and a region known to interact with RAD51 (Narod 2004, Chen 1998). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Arg866His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589478 SCV000698968 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2597G>A (p.Arg866His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Arg866 is conserved across species but is not located in a known functional domain of the Breast cancer type 1 susceptibility protein. This variant was found in 4/121324 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in multiple breast or ovarian cancer patients without strong evidence for causality (i.e. co-segregation or functional studies). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS, without evidence to independently evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics RCV000047893 SCV000839268 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589478 SCV000887648 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing
Color RCV000130531 SCV000904129 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077524 SCV000109325 uncertain significance Breast-ovarian cancer, familial 1 2009-05-28 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077524 SCV000144487 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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