ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6665A>G (p.Tyr2222Cys) (rs397507875)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221087 SCV000275312 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000221087 SCV000911088 likely benign Hereditary cancer-predisposing syndrome 2017-02-21 criteria provided, single submitter clinical testing
Counsyl RCV000410387 SCV000488385 uncertain significance Breast-ovarian cancer, familial 2 2016-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000485026 SCV000567999 uncertain significance not specified 2017-04-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6665A>G at the cDNA level, p.Tyr2222Cys (Y2222C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). Using alternate nomenclature, this variant has been previously published as BRCA2 6893A>G. This variant has been reported in at least two individuals, one with early-onset prostate cancer and another meeting NCCN testing criteria for Hereditary Breast and Ovarian Cancer syndrome (Edwards 2003, Kurian 2008). BRCA2 Tyr2222Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2222Cys occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Tyr2222Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000045012 SCV000073025 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-06 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2222 of the BRCA2 protein (p.Tyr2222Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs397507875, ExAC 0.003%). This variant has been reported in an individual affected with early onset prostate cancer (PMID: 12474142) as well as in several individuals with breast cancer (PMID: 27062684, 18779604, 27225819). This variant is also known as 6893A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52151). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mendelics RCV000045012 SCV000838845 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759647 SCV000889110 uncertain significance not provided 2017-12-27 criteria provided, single submitter clinical testing

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