5-112840951-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000038.6(APC):c.5357G>C(p.Arg1786Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5357G>C | p.Arg1786Thr | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+11979G>C | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250434Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135510
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461064Hom.: 0 Cov.: 54 AF XY: 0.00000275 AC XY: 2AN XY: 726878
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:3
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This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1786 of the APC protein (p.Arg1786Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis and colorectal cancer (PMID: 19531215, 26976419, 35534704). ClinVar contains an entry for this variant (Variation ID: 470001). 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%. 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:1
The p.R1786T variant (also known as c.5357G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 5357. The arginine at codon 1786 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration has also been reported in a Galician patient with an attenuated FAP phenotype (Gómez-Fernández N et al. BMC Med. Genet., 2009 Jun;10:57). This amino acid position is well 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at