ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.706A>G (p.Met236Val)

gnomAD frequency: 0.00001  dbSNP: rs771319430
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220492 SCV000279210 uncertain significance not provided 2019-09-16 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV001025994 SCV001188292 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-27 criteria provided, single submitter clinical testing The p.M236V variant (also known as c.706A>G), located in coding exon 7 of the FANCC gene, results from an A to G substitution at nucleotide position 706. The methionine at codon 236 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001368893 SCV001565312 uncertain significance Fanconi anemia 2021-09-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 236 of the FANCC protein (p.Met236Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 234430). 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001368893 SCV002012435 uncertain significance Fanconi anemia 2021-10-28 criteria provided, single submitter clinical testing The FANCC c.706A>G (p.Met236Val) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/9-97897765-T-C). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4
Natera, Inc. RCV001368893 SCV002081226 uncertain significance Fanconi anemia 2018-06-18 no assertion criteria provided clinical testing

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