ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2286A>T (p.Arg762Ser) (rs273898682)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111817 SCV001161570 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00166 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV001084129 SCV000075796 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132175 SCV000187254 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing The p.R762S variant (also known as c.2286A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2286. The arginine at codon 762 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported with a carrier frequency of 1 in 7051 unselected breast cancer patients and 2 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration has also been detected in Malaysian, Chinese, and Iranian women with breast cancer (Toh GT et al. PLoS ONE 2008 Apr;3(4):e2024; Cao W et al. Anat Rec (Hoboken) 2013 Feb;296(2):273-8; Sadr-Nadavi A et al. Hereditas. 2014 Jun;151(2-3):38-42; Lai KN et al. BMC Cancer, 2017 Feb;17:149; Sung PL et al. PLoS ONE, 2017 Sep;12:e0185615; Yang XR et al. Breast Cancer Res. Treat., 2017 Oct;165:687-697) as well as in healthy control populations (Suter NM et al. Cancer Epidemiol. Biomarkers Prev. 2004 Feb;13(2):181-9; Lai KN et al. BMC Cancer, 2017 Feb;17:149). This alteration has an Align-GVGD score of C0 which is predicted to have less impact on protein function (Cao W et al. Anat Rec (Hoboken) 2013 Feb;296(2):273-8). Of note, this alteration is also designated as 2405A>T in published literature. 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.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240751 SCV000265885 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Counsyl RCV000111817 SCV000489265 uncertain significance Breast-ovarian cancer, familial 1 2016-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000485167 SCV000566093 likely benign not specified 2018-01-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Health, Inc RCV000132175 SCV000903159 likely benign Hereditary cancer-predisposing syndrome 2016-10-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000047783 SCV001133522 benign not provided 2018-08-31 criteria provided, single submitter clinical testing
Mendelics RCV000111817 SCV001140578 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111817 SCV001283972 uncertain significance Breast-ovarian cancer, familial 1 2018-03-19 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111817 SCV000144367 uncertain significance Breast-ovarian cancer, familial 1 2010-09-18 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353456 SCV000591376 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Arg762Ser variant was identified in 3 of 1862 proband chromosomes (frequency 0.002) from individuals with breast or ovarian cancer (Cao 2013, Suter 2004, Thirthagiri 2008,Toh 2008) and was identified in 1 of 638 control chromosomes (frequency 0.002) from these studies. All probands from these studies were of Chinese or Malaysian descent. The variant was also identified the BIC database 3X as a variant with unknown clinical importance, and in the ClinVar database (classified with “unknown significance” by Ambry Genetics and BIC). The variant was listed in dbSNP (rs273898682) with a frequency of 0.002 (1000 Genomes project; one allele positive for variant), and in the Exome Aggregation Consortium (ExAC) database in 13 of 8654 chromosomes (frequency: 0.0001502) from a population of East Asian individuals and in 1 of 16508 chromosomes from South Asian individuals. The low frequency observed in these cohorts is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Arg762 residue is conserved in mammals; however, the variant amino acid Serine (Ser) is present in both African clawed frog and purple sea urchin, increasing the likelihood that this variant may not have clinical significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein and Toh (2008) notes that this residue occurs outside of any known functional domain; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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