ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8651A>G (p.Tyr2884Cys) (rs587781494)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129459 SCV000184229 likely benign Hereditary cancer-predisposing syndrome 2017-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign),Other strong data supporting benign classification
GeneDx RCV000481920 SCV000566819 uncertain significance not provided 2015-06-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8651A>G at the cDNA level, p.Tyr2884Cys (Y2884C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 8879A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr2884Cys 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 Tyr2884Cys occurs at a position that is not conserved and is located in the DNA binding 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 Tyr2884Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000689857 SCV000817526 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2884 of the BRCA2 protein (p.Tyr2884Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with a personal/family history of breast cancer or ovarian cancer (PMID: 28111427). ClinVar contains an entry for this variant (Variation ID: 141100). 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.

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