5-112844118-T-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000038.6(APC):āc.8524T>Gā(p.Ser2842Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.8524T>G | p.Ser2842Ala | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.229-12531T>G | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250534Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135442
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1459340Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4AN XY: 726132
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2Benign:1
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This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2842 of the APC protein (p.Ser2842Ala). This variant is present in population databases (rs587780610, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 135728). 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) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APC function (PMID: 22434720). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -
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Hereditary cancer-predisposing syndrome Uncertain:2
The p.S2842A variant (also known as c.8524T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 8524. The serine at codon 2842 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This missense variant replaces serine with alanine at codon 2842 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental study reported this variant did not affect binding of APC to PDZ domain containing partners (PMID: 22434720). This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250534 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Classic or attenuated familial adenomatous polyposis Uncertain:1
This missense variant replaces serine with alanine at codon 2842 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental study reported this variant did not affect binding of APC to PDZ domain containing partners (PMID: 22434720). This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250534 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
APC-related disorder Uncertain:1
The APC c.8524T>G variant is predicted to result in the amino acid substitution p.Ser2842Ala. To our knowledge, this variant has not been reported in individuals with APC-related conditions. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112179815-T-G) and interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/135728/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at