Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000220053 | SCV000273591 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-11 | criteria provided, single submitter | clinical testing | The p.C328R variant (also known as c.982T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 982. The cysteine at codon 328 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was detected in 1/727 pancreatic cancer probands with at least two relatives who were also diagnosed with pancreatic cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). An in vitro functional study found that this alteration does not significantly affect BRCA1 homology-directed repair activity (Lu C et al. Nat Commun. 2015 Dec;6:10086). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000231864 | SCV000289848 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-09 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 328 of the BRCA1 protein (p.Cys328Arg). This variant is present in population databases (rs748156170, gnomAD 0.005%). This missense change has been observed in individual(s) with pancreatic cancer or lung adenocarcinoma (PMID: 25356972, 26689913). This variant is also known as c.1101T>C. ClinVar contains an entry for this variant (Variation ID: 230150). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001731443 | SCV000600448 | uncertain significance | not provided | 2020-11-23 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000506531 | SCV000699323 | uncertain significance | not specified | 2021-06-26 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.982T>C (p.Cys328Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.982T>C has been reported in the literature as a VUS in individuals affected with Pancreatic cancer as well as in the TGCA cohort (example, Zhen_2014, Lu_2015, Zhan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (HDR) activity (Lu_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
Color Diagnostics, |
RCV000220053 | SCV000909394 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-03-12 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001731443 | SCV001982653 | uncertain significance | not provided | 2021-10-12 | criteria provided, single submitter | clinical testing | Observed in individuals with pancreatic cancer or lung cancer (Lu 2015, Zhen 2015); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1101T>C; This variant is associated with the following publications: (PMID: 25356972, 26689913) |
Fulgent Genetics, |
RCV002485416 | SCV002777803 | uncertain significance | Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S | 2022-03-20 | criteria provided, single submitter | clinical testing | |
University of Washington Department of Laboratory Medicine, |
RCV000220053 | SCV003846252 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |