Submissions for variant NM_000136.3(FANCC):c.228G>T (p.Trp76Cys)

dbSNP: rs876661132

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221761	SCV000279631	uncertain significance	not provided	2015-11-23	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.228G>T at the cDNA level, p.Trp76Cys (W76C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Trp76Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tryptophan and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Trp76Cys occurs at a position that is not conserved and is located in the region of interaction with RED (Gordon 2000). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether FANCC Trp76Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV003165583	SCV003856301	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.W76C variant (also known as c.228G>T), located in coding exon 2 of the FANCC gene, results from a G to T substitution at nucleotide position 228. The tryptophan at codon 76 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001833231	SCV004532884	uncertain significance	Fanconi anemia	2023-09-04	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 234633). 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. 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. This variant has not been reported in the literature in individuals affected with FANCC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 76 of the FANCC protein (p.Trp76Cys).
Natera, Inc.	RCV001833231	SCV002081293	uncertain significance	Fanconi anemia	2021-06-29	no assertion criteria provided	clinical testing