ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.20G>A (p.Arg7His) (rs144792613)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164210 SCV000214831 likely benign Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000588310 SCV000329116 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.20G>A at the cDNA level, p.Arg7His (R7H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). Using alternate nomenclature, this variant would be defined as BRCA1 139G>A. This variant has been observed in at least one individual referred for BRCA1 testing (Judkins 2005). It was demonstrated to have E3 ligase activity and BARD1 interaction similar to wildtype and was able to rescue homology-directed repair in a cell line lacking endogenous BRCA1 (Starita 2015). BRCA1 Arg7His was not observed in large population cohorts (Lek 2016). This variant is located in the RING domain and a region known to interact with BRD7 (Harte 2010, Borg 2010, Paul 2014). 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 Arg7His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000543291 SCV000635828 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 7 of the BRCA1 protein (p.Arg7His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs144792613, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 184875). This variant has been reported not to substantially affect BRCA1 protein function (PMID: 30209399, 25823446). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588310 SCV000698916 uncertain significance not provided 2017-08-03 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.20G>A (p.Arg7His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120706 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in at least one patient with HBOC without strong support for pathogenicity (Judkins_2005). A functional study (Starita_2015) reported the variant to be as proficient in homology-directed DNA repair as is the wild type BRCA1 indicating the variant to be in the neutral spectrum. In addition, multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Considering all evidence, the variant was classified as VUS-possibly benign.
Fulgent Genetics,Fulgent Genetics RCV000764129 SCV000895102 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164210 SCV000903775 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-12 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 7 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported this variant to have neutral impact on homology-directed DNA repair, BARD1 binding, E3 ubiquitin ligase and haploid cell proliferation assays (PMID: 25823446, 30209399). This variant has been reported in a breast cancer case-control study where it was detected in 2 unaffected controls and was absent in breast cancer cases (PMID: 30287823). This variant has been identified in 7/251074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Brotman Baty Institute,University of Washington RCV001072325 SCV001237685 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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