Submissions for variant NM_000136.3(FANCC):c.760A>G (p.Met254Val)

dbSNP: rs757294568

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231342	SCV000283597	uncertain significance	Fanconi anemia	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 254 of the FANCC protein (p.Met254Val). This variant is not present in population databases (gnomAD no frequency). 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: 237076). 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	RCV001026618	SCV001189038	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	clinical testing	The p.M254V variant (also known as c.760A>G), located in coding exon 7 of the FANCC gene, results from an A to G substitution at nucleotide position 760. The methionine at codon 254 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species, and valine is the reference amino acid in other 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	RCV001551720	SCV001772287	uncertain significance	not provided	2023-03-29	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Gordon2000[Book])
Sema4, Sema4	RCV000231342	SCV002535121	uncertain significance	Fanconi anemia	2021-08-10	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001274479	SCV002776246	uncertain significance	Fanconi anemia complementation group C	2022-03-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274479	SCV001458702	uncertain significance	Fanconi anemia complementation group C	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354988	SCV001549734	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Met254Val variant was not identified in the literature nor was it identified in the Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs757294568 as “With Uncertain significance allele”) and ClinVar (1x classified as uncertain significance by Invitae). The variant was identified in control databases in 1 of 120966 chromosomes at a frequency of 0.000008 (Exome Aggregation Consortium, August 8th 2016), specifically in the East Asian population in 1 of 8642 chromosomes (freq: 0.0001) and was not observed in the African, European Non-Finnish, Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Met254 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.