ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4184A>G (p.Gln1395Arg) (rs80356972)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048473 SCV000076486 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-07 criteria provided, single submitter clinical testing
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 2019-02-05 criteria provided, single submitter clinical testing The p.Q1395R variant (also known as c.4184A>G), located in coding exon 10 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4184. The glutamine at codon 1395 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in an a cohort of African American women with early-onset breast cancer (Haffty BG Ann. Oncol. 2009 Oct; 20:1653-9). This alteration was called a variant of uncertain significance by VarCall, a Bayesian hierarchical model estimating the likelihood of pathogenicity given functional data (Woods NT et al. NPJ Genom. Med. 2016 Mar;1). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193743 SCV001362809 uncertain significance not specified 2019-05-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4184A>G (p.Gln1395Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 242736 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4184A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Haffty_2009, Judkins_2005). These data do not allow any conclusion about variant significance. A functional study, Woods_2016, assessed the transcriptional activation in the presence of the variant, which was found to be about 70% of wild type activity. Then, authors assessed transcriptional activation in the presence of a PALB2 fusion protein and also found the variant to decrease transcriptional activation. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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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