Submissions for variant NM_000136.3(FANCC):c.28T>G (p.Cys10Gly)

gnomAD frequency: 0.00004  dbSNP: rs147479204

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200177	SCV000254259	uncertain significance	Fanconi anemia	2022-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 10 of the FANCC protein (p.Cys10Gly). This variant is present in population databases (rs147479204, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or family history of breast and pancreatic cancer (PMID: 14726700, 23028338). ClinVar contains an entry for this variant (Variation ID: 216287). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV000218236	SCV000278971	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, pancreatic, and other cancers (Rogers et al., 2004; Thompson et al., 2012; Martin-Morales et al., 2018); This variant is associated with the following publications: (PMID: 23028338, 30256826, 14726700, Gordon2000[Book])
Mendelics	RCV000709098	SCV000838363	uncertain significance	Fanconi anemia complementation group C	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001016913	SCV001177919	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-18	criteria provided, single submitter	clinical testing	The p.C10G variant (also known as c.28T>G), located in coding exon 1 of the FANCC gene, results from a T to G substitution at nucleotide position 28. The cysteine at codon 10 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration has been detected in an unaffected individual with a family history of pancreatic cancer (Rogers CD et al. Cancer Biol. Ther. 2004 Feb;3:167-9). It was also detected in 1/1441 breast cancer families that previously tested negative for pathogenic mutations in the BRCA1 and BRCA2 genes and it was not detected in 464 controls (Thompson ER et al. PLoS Genet. 2012 Sep;8:e1002894). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is poorly 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000218236	SCV001714905	uncertain significance	not provided	2021-01-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818485	SCV002066715	uncertain significance	not specified	2020-12-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.28T>G, in exon 2 that results in an amino acid change, p.Cys10Gly. This sequence change has been described in the gnomAD database with a low frequency of 0.005% in the European sub-population (dbSNP rs147479204). The p.Cys10Gly change has been described in an individual with breast cancer (PMID: 23028338), as well as an unaffected individual with a family history of breast and pancreatic cancer (PMID: 14726700). The p.Cys10Gly change affects a poorly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. The p.Cys10Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Cys10Gly change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV000709098	SCV002776261	uncertain significance	Fanconi anemia complementation group C	2022-03-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218236	SCV004218673	uncertain significance	not provided	2022-11-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000054 (7/128662 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individual with breast cancer (PMID: 23028338 (2012), 33471991 (2021)). The variant has also been reported in unaffected individuals (PMID: 33471991 (2021), 14726700 (2004)). 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on FANCC mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000200177	SCV002081320	uncertain significance	Fanconi anemia	2018-05-29	no assertion criteria provided	clinical testing