Submissions for variant NM_000136.3(FANCC):c.851C>T (p.Ala284Val)

gnomAD frequency: 0.00001  dbSNP: rs201281511

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658080	SCV000779851	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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])
Invitae	RCV000814395	SCV000954804	uncertain significance	Fanconi anemia	2022-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the FANCC protein (p.Ala284Val). This variant is present in population databases (rs201281511, gnomAD 0.003%). 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: 546233). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Genetic Services Laboratory, University of Chicago	RCV001816657	SCV002066665	uncertain significance	not specified	2020-11-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.851C>T, in exon 9 that results in an amino acid change, p.Ala284Val. This sequence change does not appear to have been previously described in patients with FANCC-related disorders and has been described in the gnomAD database in one individual with a low overall population frequency of 0.0004% (dbSNP rs201281511). The p.Ala284Val change affects a highly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. The p.Ala284Val substitution appears to be deleterious 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.Ala284Val change remains unknown at this time.
Ambry Genetics	RCV002406500	SCV002675452	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The p.A284V variant (also known as c.851C>T), located in coding exon 8 of the FANCC gene, results from a C to T substitution at nucleotide position 851. The alanine at codon 284 is replaced by valine, an amino acid with similar properties. This variant was reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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.
Natera, Inc.	RCV001274474	SCV001458697	uncertain significance	Fanconi anemia complementation group C	2020-09-16	no assertion criteria provided	clinical testing