Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000048473 | SCV000076486 | likely benign | Hereditary breast ovarian cancer syndrome | 2023-08-28 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000483719 | SCV000565683 | uncertain significance | not provided | 2020-01-15 | criteria provided, single submitter | clinical testing | Observed in at least one patient with early onset breast cancer (Haffty 2009); Published functional studies demonstrate no damaging effect: transcriptional activation similar to wild type (Woods 2016); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 4303A>G; This variant is associated with the following publications: (PMID: 16267036, 19491284, 21523855, 23704879, 28781887) |
Ambry Genetics | RCV000509874 | SCV000608202 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-24 | 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, |
RCV001193743 | SCV001362809 | uncertain significance | not specified | 2022-10-11 | 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. The variant alters a conserved nucleotide located in the exonic-splice region close to the the adjacent intronic splice donor site, 4/4 computational tools predict no significant impact on normal splicing. Although a slight weakening of the canonical 5' splicing donor site is predicted, to our knowledge, these observations have not been confirmed by published functional studies. This variant is also known as 4303A>G (legacy name). The variant was absent in 242736 control chromosomes (gnomAD). c.4184A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer without evidence for causality (example, Haffty_2009, Judkins_2005). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Two publications report experimental evidence evaluating an impact on protein function. 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. More recently, Foo_2021, demonstrated that this variant causes reduced homologous recombination (HR)mediated repair of DNA double-strand breaks (DSB), increased single-strand annealing (SSA), and reduced cellular resistance to DNA damaging agents. The authors concluded that this variant has functional defects and may potentially increase cancer risk or affect prognosis. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=2) and likely benign (n=1). Some submitters cite overlapping, but not identical evidence utilized in the context of this evaluation. Based on the emerging functional evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
Sharing Clinical Reports Project |
RCV000077565 | SCV000109367 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 1 | 2012-01-10 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000077565 | SCV000145007 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2004-11-25 | no assertion criteria provided | clinical testing |