ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9677A>G (p.Tyr3226Cys) (rs80359237)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045885 SCV000073898 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 3226 of the BRCA2 protein (p.Tyr3226Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs80359237, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 22034289). ClinVar contains an entry for this variant (Variation ID: 52890). 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: "Tolerated"; 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.
Ambry Genetics RCV000165822 SCV000216569 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000369165 SCV000329148 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9677A>G at the cDNA level, p.Tyr3226Cys (Y3226C) 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 9905A>G. This variant has been observed in at least one individual with breast cancer (Fackenthal 2012). BRCA2 Tyr3226Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Tyr3226Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000114153 SCV000784904 uncertain significance Breast-ovarian cancer, familial 2 2017-02-08 criteria provided, single submitter clinical testing
Mendelics RCV000045885 SCV000838911 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000369165 SCV000889187 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
Color RCV000165822 SCV000903966 likely benign Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000114153 SCV000147698 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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