rs587782794
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_001048174.2(MUTYH):c.1410G>C(p.Gln470His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. Q470R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001048174.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.1494G>C | p.Gln498His | missense_variant | 15/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.1410G>C | p.Gln470His | missense_variant | 15/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1494G>C | p.Gln498His | missense_variant | 15/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.1410G>C | p.Gln470His | missense_variant | 15/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000824 AC: 2AN: 242830Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 131136
GnomAD4 exome AF: 0.00000961 AC: 14AN: 1457260Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 724394
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 13, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 27, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498His). This variant is present in population databases (rs587782794, gnomAD 0.002%). This missense change has been observed in individual(s) with rectal cancer (PMID: 16645203). ClinVar contains an entry for this variant (Variation ID: 142884). 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 tolerated. 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 | All of Us Research Program, National Institutes of Health | Dec 15, 2023 | This missense variant replaces glutamine with histidine at codon 498 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with rectal cancer (PMID: 16645203), or thyroid cancer (PMID: 29684080). This variant has been identified in 2/242830 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. - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 15, 2022 | This missense variant replaces glutamine with histidine at codon 498 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with rectal cancer (PMID: 16645203), or thyroid cancer (PMID: 29684080). This variant has been identified in 2/242830 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 | Feb 24, 2023 | The p.Q498H variant (also known as c.1494G>C), located in coding exon 15 of the MUTYH gene, results from a G to C substitution at nucleotide position 1494. The glutamine at codon 498 is replaced by histidine, an amino acid with highly similar properties. This alteration was previously reported in a 42 year-old with rectal cancer and no family history of colorectal cancer (Görgens H et al. J Mol Diagn 2006 May; 8(2):178-82). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 03, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2020 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of early-onset rectal cancer (Grgens 2006); This variant is associated with the following publications: (PMID: 24834277, 21061173, 16645203, 25525159) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at