chr5-112835165-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000038.6(APC):c.1958G>T(p.Arg653Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R653G) has been classified as Pathogenic.
Frequency
Consequence
NM_000038.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.1958G>T | p.Arg653Met | missense_variant, splice_region_variant | 15/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1958G>T | p.Arg653Met | missense_variant, splice_region_variant | 15/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 03, 2023 | This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | This sequence change affects codon 653 of the APC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the APC protein. This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with familial adenomatous polyposis (PMID: 19036155, 20685668, 23159591, 25590978, 33769591). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411463). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in exon 15 skipping (PMID: 20685668). This variant disrupts the c.1958G nucleotide in the APC gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18199528, 20685668, 24599579, 25590978). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2018 | The c.1958G>T pathogenic mutation (also known as p.R653M), located in coding exon 14 of the APC gene, results from a G to T substitution at nucleotide position 1958. The amino acid change results in arginine to methionine at codon 653, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 14, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in multiple patients with personal and families histories of colorectal cancer and/or polyposis (Nilbert M et al. BMC Med. Genet. 2008;9:101; Inra JA et al. Genet. Med. 2015 Oct;17(10):815-21). Additionally, a mutation at the same nucleotide position (c.1958G>C) was described in a patient with familial adenomatous polyposis, and abnormal splicing was confirmed upon mRNA transcript analysis (Tao H et al. BMC Res Notes 2010;3:305). This alteration appears to cosegregate with disease in one family affected with familial adenomatous polyposis in our internal cohort (Ambry internal data). Based on the available evidence, c.1958G>T is classified as a pathogenic mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at