5-112835024-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000038.6(APC):c.1817T>C(p.Ile606Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,830 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. I606M) has been classified 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.1817T>C | p.Ile606Thr | missense_variant | 15/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1817T>C | p.Ile606Thr | missense_variant | 15/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135808
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727216
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 606 of the APC protein (p.Ile606Thr). This variant is present in population databases (rs781337455, gnomAD 0.0009%). 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: 537509). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2023 | The p.I606T variant (also known as c.1817T>C), located in coding exon 14 of the APC gene, results from a T to C substitution at nucleotide position 1817. The isoleucine at codon 606 is replaced by threonine, an amino acid with similar properties. This alteration was also detected on a 25-gene panel test in a woman of Western/Northern European ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at