ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6281A>G (p.Tyr2094Cys) (rs397507838)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580567 SCV000683766 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000759639 SCV000565970 uncertain significance not provided 2016-12-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6281A>G at the cDNA level, p.Tyr2094Cys (Y2094C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant, also known as BRCA2 6509A>G using alternate nomenclature, has been reported in at least one individual with breast cancer (Jakubowska 2002). BRCA2 Tyr2094Cys was not observed at significant allele frequency in 1000 Genomes, and was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2094Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Tyr2094Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America 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 RCV000709324 SCV000838834 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486364 SCV000600688 uncertain significance not specified 2016-08-17 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
Sharing Clinical Reports Project (SCRP) RCV000083125 SCV000115199 uncertain significance Breast-ovarian cancer, familial 2 2012-07-05 no assertion criteria provided clinical testing

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