ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.20G>A (p.Arg7His) (rs144792613)

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Total submissions: 6
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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 Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000164210 SCV000903775 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-28 criteria provided, single submitter clinical testing
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
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000543291 SCV000635828 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-01-13 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 a BRCA1-related disease. However, a different nucleotide change (c.19C>T) resulting in the same amino acid change as this variant (p.Arg7His) has been reported in individuals with breast cancer (PMID: 23961350, 23192404). ClinVar contains an entry for this variant (Variation ID: 184875). Experimental evidence shows this variant does not impact on  BRCA1 protein function for homology directed repair activity, E3 ligase function and BARD1 protein interaction (PMID: 25823446). In summary, this variant is a rare missense change with experimental evidence that suggests it does not impact BRAC1 protein function but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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