Submissions for variant NM_000136.3(FANCC):c.1406C>T (p.Thr469Met)

gnomAD frequency: 0.00005  dbSNP: rs149917017

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487102	SCV000566574	uncertain significance	not provided	2024-04-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with ovarian cancer (PMID: 32546565); This variant is associated with the following publications: (PMID: 32546565)
Mendelics	RCV000988195	SCV001137832	uncertain significance	Fanconi anemia complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001011411	SCV001171729	likely benign	Hereditary cancer-predisposing syndrome	2024-03-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247526	SCV001420953	uncertain significance	Fanconi anemia	2024-07-24	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 469 of the FANCC protein (p.Thr469Met). This variant is present in population databases (rs149917017, 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: 419042). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328458	SCV001519599	uncertain significance	not specified	2021-03-08	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.1406C>T (p.Thr469Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251262 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (5.2e-05 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1406C>T in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002481503	SCV002783165	uncertain significance	Fanconi anemia complementation group C	2024-03-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000487102	SCV005195463	uncertain significance	not provided		criteria provided, single submitter	not provided
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487102	SCV005625564	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	The FANCC c.1406C>T (p.Thr469Met) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 32546565 (2021)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant has also been observed in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.00012 (3/24952 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.
GenomeConnect, ClinGen	RCV000487102	SCV002074997	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-21-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV001247526	SCV002081148	uncertain significance	Fanconi anemia	2018-11-15	no assertion criteria provided	clinical testing