ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6995G>A (p.Cys2332Tyr) (rs786202536)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165386 SCV000216113 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000485577 SCV000568068 uncertain significance not provided 2015-09-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6995G>A at the cDNA level, p.Cys2332Tyr (C2332Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). Using alternate nomenclature, this variant would be defined as BRCA2 7223G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Cys2332Tyr 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 Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Cys2332Tyr occurs at a position that is conserved in mammals and is not located in a known functional domain (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Cys2332Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000701592 SCV000830400 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 2332 of the BRCA2 protein (p.Cys2332Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 185885). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000165386 SCV000906542 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing

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