Submissions for variant NM_000136.3(FANCC):c.1493C>T (p.Ala498Val)

gnomAD frequency: 0.00004  dbSNP: rs730881725

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160489	SCV000211054	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or ovarian cancer (Thompson et al., 2012; Song et al., 2021); This variant is associated with the following publications: (PMID: 32546565, 23028338)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204351	SCV000260179	uncertain significance	Fanconi anemia	2023-12-29	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 498 of the FANCC protein (p.Ala498Val). This variant is present in population databases (rs730881725, gnomAD 0.005%). This missense change has been observed in individual(s) with family history of breast cancer (PMID: 23028338). ClinVar contains an entry for this variant (Variation ID: 182488). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV001011857	SCV001172231	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	The p.A498V variant (also known as c.1493C>T), located in coding exon 13 of the FANCC gene, results from a C to T substitution at nucleotide position 1493. The alanine at codon 498 is replaced by valine, an amino acid with similar properties. This alteration was detected in a cohort of 438 breast cancer families (Thompson ER et al. PLoS Genet, 2012 Sep;8:e1002894). This amino acid position is not well 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.
Illumina Laboratory Services, Illumina	RCV001167958	SCV001330509	uncertain significance	Fanconi anemia complementation group C	2017-05-15	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001167958	SCV002526040	uncertain significance	Fanconi anemia complementation group C	2022-09-28	criteria provided, single submitter	clinical testing	The FANCC c.1493C>T (p.Ala498Val) missense change has a maximum subpopulation frequency of 0.0021% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer (PMID: 23028338) and ovarian cancer (PMID: 32546565). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Sema4, Sema4	RCV000204351	SCV002535093	uncertain significance	Fanconi anemia	2021-11-09	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001167958	SCV002782107	uncertain significance	Fanconi anemia complementation group C	2021-11-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001167958	SCV001457636	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	RCV001167958	SCV001549863	uncertain significance	Fanconi anemia complementation group C		no assertion criteria provided	clinical testing	The FANCC p.Ala498Val variant was identified in 1 of 2882 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was not identified in 928 control chromosomes from healthy individuals (Thompson 2012). The variant was also identified in dbSNP (ID: rs730881725) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 6 of 277174 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 6 of 126674 chromosomes (freq: 0.00005), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala498 residue is not conserved in mammals and four out of five 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.