Submissions for variant NM_000136.3(FANCC):c.1259C>T (p.Thr420Met)

gnomAD frequency: 0.00010  dbSNP: rs779261511

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519962	SCV000616933	uncertain significance	not provided	2023-03-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27149842, Gordon2000[Book])
Mendelics	RCV000988202	SCV001137839	uncertain significance	Fanconi anemia complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001010616	SCV001170841	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-18	criteria provided, single submitter	clinical testing	The p.T420M variant (also known as c.1259C>T), located in coding exon 12 of the FANCC gene, results from a C to T substitution at nucleotide position 1259. The threonine at codon 420 is replaced by methionine, an amino acid with similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242520	SCV001415614	uncertain significance	Fanconi anemia	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 420 of the FANCC protein (p.Thr420Met). This variant is present in population databases (rs779261511, gnomAD 0.03%). 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: 449129). 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.
Fulgent Genetics, Fulgent Genetics	RCV002497008	SCV002814804	uncertain significance	Fanconi anemia complementation group C	2024-04-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000519962	SCV004218662	uncertain significance	not provided	2023-05-22	criteria provided, single submitter	clinical testing	In a large scale breast cancer association study, the variant was observed in unaffected individuals and not among the breast cancer cases (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCC)). The frequency of this variant in the general population, 0.00028 (7/24962 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV001242520	SCV002081169	uncertain significance	Fanconi anemia	2018-05-28	no assertion criteria provided	clinical testing