rs767747402
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001048174.2(MUTYH):c.1346C>T(p.Thr449Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,886 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. T449K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001048174.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.1430C>T | p.Thr477Met | missense_variant | 14/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.1346C>T | p.Thr449Met | missense_variant | 14/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1430C>T | p.Thr477Met | missense_variant | 14/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.1346C>T | p.Thr449Met | missense_variant | 14/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251488Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 477 of the MUTYH protein (p.Thr477Met). This variant is present in population databases (rs767747402, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 18515411). This variant is also known as c.1421C>T (T474M). ClinVar contains an entry for this variant (Variation ID: 188159). 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. 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 | Counsyl | May 17, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 04, 2023 | This missense variant replaces threonine with methionine at codon 477 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251488 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 | clinical testing | Baylor Genetics | Nov 23, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 01, 2023 | This missense variant replaces threonine with methionine at codon 477 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 4/251488 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 | clinical testing | Ambry Genetics | Mar 04, 2022 | The p.T477M variant (also known as c.1430C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide position 1430. The threonine at codon 477 is replaced by methionine, an amino acid with similar properties. This alteration, designated as p.T474M, was identified in one individual from a multiple adenoma cohort; however, the individual also carried two pathogenic MUTYH mutations and phase of the alterations (cis or trans) was not determined (Dallosso AR et al. Gut. 2008 Sep;57:1252-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Co-occurred with two pathogenic MUTYH variants in an individual with colorectal cancer, multiple colorectal adenomas, and gastric antral adenomas (Dallosso et al., 2008); Also known as MUTYH Thr474Met; This variant is associated with the following publications: (PMID: 23108399, 18515411) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at