rs745621828
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000136.3(FANCC):āc.823T>Cā(p.Phe275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000136.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.823T>C | p.Phe275Leu | missense_variant | 8/15 | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.823T>C | p.Phe275Leu | missense_variant | 8/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251440Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461776Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727170
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74380
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 08, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 275 of the FANCC protein (p.Phe275Leu). This variant is present in population databases (rs745621828, gnomAD 0.003%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 15695377). ClinVar contains an entry for this variant (Variation ID: 219885). 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic cancer (Couch et al., 2005); This variant is associated with the following publications: (PMID: Gordon2000[Book], 15695377) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 11, 2022 | The frequency of this variant in the general population, 0.000026 (3/113742 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pancreatic cancer (PMID: 15695377 (2005)) and an individual with breast cancer (PMID: 34445631 (2021)). In a large breast cancer association study, the variant was reported in both affected and unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/FANCC). 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. - |
Fanconi anemia complementation group C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 21, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 05, 2023 | The p.F275L variant (also known as c.823T>C), located in coding exon 7 of the FANCC gene, results from a T to C substitution at nucleotide position 823. The phenylalanine at codon 275 is replaced by leucine, an amino acid with highly similar properties. This alteration (designated 1078T>C) was identified in 1/421 pancreatic cancer cases and 0/654 controls. (Couch FJ et al. Cancer Res. 2005 Jan;65:383-6). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at