ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9098C>T (p.Thr3033Ile) (rs431825374)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166290 SCV000217073 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000269121 SCV000329146 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9098C>T at the cDNA level, p.Thr3033Ile (T3033I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 9326C>T. This variant has been reported in individuals with personal and/or family history of breast cancer and ovarian cancer, and exhibited an intermediate level of homology-directed repair (HDR) activity in a cell-based functional assay (Guidugli 2013, Eccles 2015, Couch 2015, Guidugli 2018). BRCA2 Thr3033Ile was not observed in large population cohorts (Lek 2016). BRCA2 Thr3033Ile is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Thr3033Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000166290 SCV000684023 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Invitae RCV000689164 SCV000816804 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 3033 of the BRCA2 protein (p.Thr3033Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with breast cancer and ovarian cancer (PMID: 25452441, 26153499). ClinVar contains an entry for this variant (Variation ID: 96879). Experimental studies have shown that this missense change had no significant effect on homology directed repair activity (PMID: 23108138, 24323938, 29394989). 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.
Sharing Clinical Reports Project (SCRP) RCV000083000 SCV000115074 uncertain significance Breast-ovarian cancer, familial 2 2009-04-08 no assertion criteria provided clinical testing

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