Submissions for variant NM_000136.3(FANCC):c.770T>C (p.Leu257Pro)

gnomAD frequency: 0.00002  dbSNP: rs1060502515

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000464277	SCV000549958	uncertain significance	Fanconi anemia	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 257 of the FANCC protein (p.Leu257Pro). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 409655). 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 expected to disrupt FANCC protein function with a positive 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293620	SCV001482240	uncertain significance	not specified	2021-02-12	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.770T>C (p.Leu257Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251426 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.770T>C in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002402273	SCV002674842	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-14	criteria provided, single submitter	clinical testing	The p.L257P variant (also known as c.770T>C), located in coding exon 7 of the FANCC gene, results from a T to C substitution at nucleotide position 770. The leucine at codon 257 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477980	SCV004218691	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00017 (6/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000464277	SCV002081222	uncertain significance	Fanconi anemia	2017-10-16	no assertion criteria provided	clinical testing