Submissions for variant NM_000136.3(FANCC):c.1374A>C (p.Arg458Ser) (rs56394801)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115342	SCV000149251	uncertain significance	not provided	2018-07-11	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.1374A>C at the cDNA level, p.Arg458Ser (R458S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FANCC Arg458Ser was observed at an allele frequency of 0.10% (25/24020) in individuals of African ancestry 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 FANCC Arg458Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics	RCV000709080	SCV000838342	uncertain significance	Fanconi anemia, complementation group C	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000805530	SCV000945488	uncertain significance	Fanconi anemia	2018-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with serine at codon 458 of the FANCC protein (p.Arg458Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs56394801, ExAC 0.1%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 127532). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly 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.