rs756336949
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_000038.6(APC):c.1243G>A(p.Ala415Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A415A) has been classified as Benign.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.1243G>A | p.Ala415Thr | missense_variant | 10/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1243G>A | p.Ala415Thr | missense_variant | 10/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250582Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135372
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461758Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727174
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 415 of the APC protein (p.Ala415Thr). This variant is present in population databases (rs756336949, gnomAD 0.009%). This missense change has been observed in individual(s) with endometrial cancer and colon cancer (PMID: 27443514, 27978560). ClinVar contains an entry for this variant (Variation ID: 217920). 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 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 23, 2024 | The p.A415T variant (also known as c.1243G>A), located in coding exon 9 of the APC gene, results from a G to A substitution at nucleotide position 1243. The alanine at codon 415 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a female patient with a mismatch repair proficient sigmoid colorectal cancer at age 47 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). It has also been reported in a cohort of 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 23, 2023 | This missense variant replaces alanine with threonine at codon 415 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 5/250582 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 21, 2021 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 03, 2020 | DNA sequence analysis of the APC gene demonstrated a sequence change, c.1243G>A, in exon 10 that results in an amino acid change, p.Ala415Thr. This sequence change has been described in the gnomAD database in five individuals with an overall population frequency of 0.002% (dbSNP rs756336949). The p.Ala415Thr change has been reported in individuals with endometrial cancer and colon cancer (PMIDs: 27443514, 27978560). The p.Ala415Thr change affects a highly conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala415Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala415Thr change remains unknown at this time. - |
Uncertain significance, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 27978560, 25980754) - |
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces alanine with threonine at codon 415 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer (PMID: 27443514) and early-onset colon cancer (PMID: 27978560). This variant has been identified in 5/250582 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at