9-95101823-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000136.3(FANCC):c.1561G>A(p.Glu521Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E521A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000136.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.1561G>A | p.Glu521Lys | missense_variant | 15/15 | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.1561G>A | p.Glu521Lys | missense_variant | 15/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251010Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135718
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461704Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727144
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74354
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 12, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 521 of the FANCC protein (p.Glu521Lys). This variant is present in population databases (rs752855423, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 30613976). ClinVar contains an entry for this variant (Variation ID: 234512). 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: "Tolerated"; 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. - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 29, 2022 | DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.1561G>A, in exon 15 results in an amino acid change, p.Glu521Lys. This sequence change has been previously described in an individual with male breast cancer (PMID: 30613976). This sequence change has been described in the gnomAD database with a global population frequency of 0.002% (dbSNP rs752855423). The p.Glu521Lys change affects a highly 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.Glu521Lys substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu521Lys change remains unknown at this time. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with male breast cancer (Rizzolo et al., 2019); This variant is associated with the following publications: (PMID: 12750283, 24163242, 29599312, 30613976, Gordon2000[Book], 15277238) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2024 | The p.E521K variant (also known as c.1561G>A), located in coding exon 14 of the FANCC gene, results from a G to A substitution at nucleotide position 1561. The glutamic acid at codon 521 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly 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