Submissions for variant NM_000136.3(FANCC):c.1241C>T (p.Ser414Leu)

gnomAD frequency: 0.00005  dbSNP: rs200719554

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000808401	SCV000948510	uncertain significance	Fanconi anemia	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 414 of the FANCC protein (p.Ser414Leu). This variant is present in population databases (rs200719554, gnomAD 0.003%). 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: 652771). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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	RCV001010523	SCV001170739	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-24	criteria provided, single submitter	clinical testing	The p.S414L variant (also known as c.1241C>T), located in coding exon 12 of the FANCC gene, results from a C to T substitution at nucleotide position 1241. The serine at codon 414 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well 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.
GeneDx	RCV002298781	SCV002588173	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: Gordon2000[Book])
Fulgent Genetics, Fulgent Genetics	RCV001273989	SCV002788236	uncertain significance	Fanconi anemia complementation group C	2022-05-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002298781	SCV004218661	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (3/113722 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a large breast cancer association study in individuals affected with breast cancer and in unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/FANCC). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV001273989	SCV001457650	uncertain significance	Fanconi anemia complementation group C	2020-09-16	no assertion criteria provided	clinical testing