rs763151358
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_021922.3(FANCE):c.598C>T(p.Arg200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200H) has been classified as Uncertain significance.
Frequency
Consequence
NM_021922.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCE | NM_021922.3 | c.598C>T | p.Arg200Cys | missense_variant | 2/10 | ENST00000229769.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCE | ENST00000229769.3 | c.598C>T | p.Arg200Cys | missense_variant | 2/10 | 1 | NM_021922.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000724 AC: 11AN: 152022Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000598 AC: 15AN: 250994Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135706
GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461766Hom.: 0 Cov.: 39 AF XY: 0.0000454 AC XY: 33AN XY: 727166
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152140Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74398
ClinVar
Submissions by phenotype
Carcinoma of colon Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer | Nov 01, 2015 | Variant detected by whole exome sequencing in a family presenting aggregation mainly for colorectal cancer but also for breast cancer - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2023 | Variant summary: FANCE c.598C>T (p.Arg200Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250994 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCE causing Fanconi Anemia (6e-05 vs 0.00048), allowing no conclusion about variant significance. c.598C>T has been reported in the literature in individuals affected with Colon cancer, Breast cancer and other unspecified childhood cancer, without strong evidence for causality (example, Esteban-Jurado_2016, Sylvester_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. 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: 27165003, 34687117). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Fanconi anemia complementation group E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 200 of the FANCE protein (p.Arg200Cys). This variant is present in population databases (rs763151358, gnomAD 0.04%). This missense change has been observed in individual(s) with colorectal cancer and breast cancer (PMID: 27165003). ClinVar contains an entry for this variant (Variation ID: 221623). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at