1-45331757-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001048174.2(MUTYH):c.1006C>T(p.Arg336Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,902 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. R336H) 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.1006C>T | p.Arg336Cys | missense_variant | Exon 12 of 16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
ENSG00000288208 | ENST00000671898.1 | n.1594C>T | non_coding_transcript_exon_variant | Exon 16 of 21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249872Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135358
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461680Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727134
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | This missense variant replaces arginine with cysteine at codon 364 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 an individual affected with endometrial cancer in the literature (PMID: 27443514). This variant has been identified in 2/249872 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 | Labcorp Genetics (formerly Invitae), Labcorp | Nov 14, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 364 of the MUTYH protein (p.Arg364Cys). This variant is present in population databases (rs151316420, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 156508). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2023 | This missense variant replaces arginine with cysteine at codon 364 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 an individual affected with endometrial cancer in the literature (PMID: 27443514). This variant has been identified in 2/249872 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 | May 30, 2024 | The p.R364C variant (also known as c.1090C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1090. The arginine at codon 364 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 11;29:1381-1389). This amino acid position is not well 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. - |
Carcinoma of colon Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with endometrial cancer in published literature (Ring et al., 2016); This variant is associated with the following publications: (PMID: 27443514) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at