Submissions for variant NM_000136.3(FANCC):c.745A>G (p.Ser249Gly)

gnomAD frequency: 0.00009  dbSNP: rs539583288

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484872	SCV000568875	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000803094	SCV000942953	uncertain significance	Fanconi anemia	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 249 of the FANCC protein (p.Ser249Gly). This variant is present in population databases (rs539583288, gnomAD 0.02%). 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: 420182). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FANCC 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.
Ambry Genetics	RCV001026459	SCV001188845	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.S249G variant (also known as c.745A>G), located in coding exon 7 of the FANCC gene, results from an A to G substitution at nucleotide position 745. The serine at codon 249 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly 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.
Sema4, Sema4	RCV000803094	SCV002535119	uncertain significance	Fanconi anemia	2021-07-27	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001274481	SCV002815708	uncertain significance	Fanconi anemia complementation group C	2022-04-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484872	SCV004218690	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00024 (6/24956 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV001274481	SCV001458704	uncertain significance	Fanconi anemia complementation group C	2020-09-16	no assertion criteria provided	clinical testing