chr5-112840326-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000038.6(APC):āc.4732T>Cā(p.Cys1578Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 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 Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.4732T>C | p.Cys1578Arg | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+11354T>C | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461880Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:1
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1578 of the APC protein (p.Cys1578Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with polyposis and colon cancer (external communication, internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 639656). Invitae Evidence 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 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 APC protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C1578R variant (also known as c.4732T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 4732. The cysteine at codon 1578 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been observed in individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). Another alteration at the same codon, p.C1578G (c.4732T>G), has been detected in multiple individuals with colorectal polyposis, and it is located in a conserved SAMP repeat that functions as an Axin binding domain (Azzopardi et al. Cancer Res. 2008 Jan;68:358-63; Minde DP et al. Mol. Cancer. 2011 Aug;10:101; Spink KE et al. EMBO J. 2000 May;19:2270–9; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at