ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5057A>G (p.His1686Arg) (rs730882166)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509750 SCV000607981 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification,Well-characterized mutation at same position
Division Human Genetics,Medical University Innsbruck RCV000162048 SCV000212004 pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
GeneDx RCV000483050 SCV000568402 likely pathogenic not provided 2018-04-05 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5057A>G at the cDNA level, p.His1686Arg (H1686R) 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 5176A>G. In a functional study, BRCA1 His1686Arg displayed impaired embryonic growth complementation, and was determined to be deleterious based on a cisplatin sensitivity assay (Bouwman 2013). In addition, this variant has been shown to segregate with BRCA1-associated cancers by another clinical laboratory (ClinVar SCV000549351.2). BRCA1 His1686Arg was not observed in large population cohorts (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA1 His1686Arg is located in the BRCT 1 domain and a region known to interact with multiple other proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be likely pathogenic.
Invitae RCV000468314 SCV000549351 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1686 of the BRCA1 protein (p.His1686Arg). The histidine residue is highly 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 an individual affected with breast cancer (PMID: 25452441). It has also been shown to segregate with BRCA1-related cancers in a single family (Invitae). ClinVar contains an entry for this variant (Variation ID: 183179). Experimental studies have shown that BRCA1 protein with this missense change is unable to functionally complement BRCA1-deficient mouse embryonic stem cells in vitro (PMID: 23867111). A different missense substitution at this codon (p.His1686Gln) has been determined to be likely pathogenic (PMID: 18757339, 12496477). This suggests that the histidine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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