Submissions for variant NM_000136.3(FANCC):c.800A>G (p.Asn267Ser) (rs200854639)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160479	SCV000211044	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.800A>G at the cDNA level, p.Asn267Ser (N267S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Asn267Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Hsp70 binding domain and the GRP94 domain (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 Asn267Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000233995	SCV000283598	uncertain significance	Fanconi anemia	2018-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with serine at codon 267 of the FANCC protein (p.Asn267Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs200854639, ExAC 0.003%) but has not been reported in the literature in individuals with a FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 182478). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000562231	SCV000673327	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-11	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)