ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6281A>G (p.Tyr2094Cys)

gnomAD frequency: 0.00001  dbSNP: rs397507838
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759639 SCV000565970 uncertain significance not provided 2020-06-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast and other cancers (Jakubowska 2002, Wong-Brown 2015); This variant is associated with the following publications: (PMID: 26269718, 25682074, 12373604)
Color Diagnostics, LLC DBA Color Health RCV000580567 SCV000683766 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 2094 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a few individuals affected with breast cancer (PMID: 12372604, 25682074). This variant has been identified in 3/275116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics RCV000709324 SCV000838834 uncertain significance Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759639 SCV000889096 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000486364 SCV000918878 uncertain significance not specified 2018-03-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6281A>G (p.Tyr2094Cys) results in a non-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 allele was found at a frequency of 1.1e-05 in 270120 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (1.1e-05 vs 0.00075), allowing no conclusion about variant significance. c.6281A>G has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer, but also was found in her unaffected sister (Jakubowska 2002). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (i.e. in UMD: BRCA1 c.1504_1508delTTAAA, p.Leu502AlafsX2; and in an internal sample: BRCA1 c.5152+5G>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
Mendelics RCV000083125 SCV001139141 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000709324 SCV001511656 uncertain significance Hereditary breast ovarian cancer syndrome 2023-02-17 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2094 of the BRCA2 protein (p.Tyr2094Cys). This variant is present in population databases (rs397507838, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and pancreatic cancer (PMID: 12373604, 25682074, 30040829). ClinVar contains an entry for this variant (Variation ID: 52046). 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 BRCA2 protein function. 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.
Ambry Genetics RCV000580567 SCV002660907 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-01 criteria provided, single submitter clinical testing The p.Y2094C variant (also known as c.6281A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6281. The tyrosine at codon 2094 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in a family with early-onset breast and stomach cancers (Jakubowska A et al. Br J Cancer. 2002 Oct 7;87(8):888-91). This amino acid position is poorly 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV003225719 SCV003806809 uncertain significance Fanconi anemia complementation group D1 2022-12-22 criteria provided, single submitter clinical testing ACMG classification criteria: PS4 supporting, PM2 moderated, BP4 supporting
University of Washington Department of Laboratory Medicine, University of Washington RCV000580567 SCV003852390 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).
Sharing Clinical Reports Project (SCRP) RCV000083125 SCV000115199 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2012-07-05 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.