Submissions for variant NM_000136.3(FANCC):c.823T>C (p.Phe275Leu)

gnomAD frequency: 0.00001  dbSNP: rs745621828

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204906	SCV000260011	uncertain significance	Fanconi anemia	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 275 of the FANCC protein (p.Phe275Leu). This variant is present in population databases (rs745621828, gnomAD 0.003%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 15695377). ClinVar contains an entry for this variant (Variation ID: 219885). 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 with a negative predictive value of 80%. 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.
GeneDx	RCV000485118	SCV000566691	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic cancer (Couch et al., 2005); This variant is associated with the following publications: (PMID: Gordon2000[Book], 15695377)
Ambry Genetics	RCV000572325	SCV000673300	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-05	criteria provided, single submitter	clinical testing	The p.F275L variant (also known as c.823T>C), located in coding exon 7 of the FANCC gene, results from a T to C substitution at nucleotide position 823. The phenylalanine at codon 275 is replaced by leucine, an amino acid with highly similar properties. This alteration (designated 1078T>C) was identified in 1/421 pancreatic cancer cases and 0/654 controls. (Couch FJ et al. Cancer Res. 2005 Jan;65:383-6). 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.
Fulgent Genetics, Fulgent Genetics	RCV002500646	SCV002814040	uncertain significance	Fanconi anemia complementation group C	2021-07-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485118	SCV004218694	uncertain significance	not provided	2022-11-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000026 (3/113742 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pancreatic cancer (PMID: 15695377 (2005)) and an individual with breast cancer (PMID: 34445631 (2021)). In a large breast cancer association study, the variant was reported in both affected and 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.	RCV000204906	SCV002081216	uncertain significance	Fanconi anemia	2019-02-08	no assertion criteria provided	clinical testing