Submissions for variant NM_000136.3(FANCC):c.29G>A (p.Cys10Tyr)

gnomAD frequency: 0.00019  dbSNP: rs143152201

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656849	SCV000149257	likely benign	not provided	2020-11-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28717660, 28767289, 26689913, 29021619)
Invitae	RCV000233348	SCV000283589	uncertain significance	Fanconi anemia	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 10 of the FANCC protein (p.Cys10Tyr). This variant is present in population databases (rs143152201, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127538). 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.
Eurofins Ntd Llc (ga)	RCV000656849	SCV000345144	uncertain significance	not provided	2016-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567825	SCV000673308	likely benign	Hereditary cancer-predisposing syndrome	2020-10-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Mendelics	RCV000709097	SCV000838362	uncertain significance	Fanconi anemia complementation group C	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000709097	SCV001330589	uncertain significance	Fanconi anemia complementation group C	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656849	SCV002010155	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818266	SCV002066058	uncertain significance	not specified	2020-03-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.29G>A, in exon 2 that results in an amino acid change, p.Cys10Tyr. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the South Asian sub-population (dbSNP rs143152201). The p.Cys10Tyr change has been reported in individuals with breast cancer, pancreatic cancer, low-grade glioma, and acute myeloid leukemia (PMID: 26689913; Lu 2015, Cabanillas 2017). The p.Cys10Tyr change affects a poorly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys10Tyr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Cys10Tyr change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818266	SCV004223160	uncertain significance	not specified	2023-11-27	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.29G>A (p.Cys10Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 250830 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.0005 vs 0.0018), allowing no conclusion about variant significance. c.29G>A has been reported in the literature in individuals affected with pancreatic cancer, prostate cancer and other GI cancer, without strong evidence for causality (example, Bhai_2021, Shindo_2017) . In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 53/60466 cases and 46/53461 controls (Dorling_2021 through LOVD).These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 28767289, 33471991). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS=6, Likely benign=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358189	SCV001553861	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Cys10Tyr variant was identified in 1 of 72 proband chromosomes (frequency: 0.01) from individuals with a personal and/or family history of cancer (Cabanillas 2017). The variant was also identified in dbSNP (ID: rs143152201) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx and three other submitters), and in LOVD 3.0. The variant was identified in control databases in 129 of 276522 chromosomes at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 4 of 6454 chromosomes (freq: 0.0006), Latino in 3 of 34402 chromosomes (freq: 0.00009), European in 59 of 126134 chromosomes (freq: 0.0005), Ashkenazi Jewish in 4 of 10132 chromosomes (freq: 0.0004), Finnish in 13 of 25776 chromosomes (freq: 0.0005), and South Asian in 46 of 30778 chromosomes (freq: 0.002), while the variant was not observed in the African or East Asian populations. The p.Cys10 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.