ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1259C>T (p.Thr420Met) (rs779261511)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519962 SCV000616933 uncertain significance not provided 2018-02-12 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1259C>T at the cDNA level, p.Thr420Met (T420M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a colon tumor (Giannakis 2016). FANCC Thr420Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with Hsp70 (Gordon 2000). 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 FANCC Thr420Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000988202 SCV001137839 uncertain significance Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001010616 SCV001170841 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001242520 SCV001415614 uncertain significance Fanconi anemia 2019-05-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 420 of the FANCC protein (p.Thr420Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with FANCC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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