ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4184A>G (p.Gln1395Arg) (rs80356972)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048473 SCV000076486 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 1395 of the BRCA1 protein (p.Gln1395Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine 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: 19491284). ClinVar contains an entry for this variant (Variation ID: 55127). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000483719 SCV000565683 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4184A>G at the cDNA level, p.Gln1395Arg (Q1395R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). Using alternate nomenclature, this variant would be defined as BRCA1 4303A>G. This variant was observed in at least one patient with early onset breast cancer and was found in a mammalian two-hybrid assay to result in transcriptional activation relatively similar to wild type (Haffty 2009, Woods 2016). BRCA1 Gln1395Arg was not observed in large population cohorts (Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln1395Arg is located in the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Paul 2014). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect, and multiple splicing models predict that this variant may damage the natural splice donor site at intron 11. However, in the absence of RNA or further functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA1 Gln1395Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509874 SCV000608202 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Sharing Clinical Reports Project (SCRP) RCV000077565 SCV000109367 likely benign Breast-ovarian cancer, familial 1 2012-01-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077565 SCV000145007 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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