rs1064793656
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001048174.2(MUTYH):c.1430G>A(p.Cys477Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. C477G) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.1514G>A | p.Cys505Tyr | missense_variant | 15/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.1430G>A | p.Cys477Tyr | missense_variant | 15/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1514G>A | p.Cys505Tyr | missense_variant | 15/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.1430G>A | p.Cys477Tyr | missense_variant | 15/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1457222Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4AN XY: 724368
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 505 of the MUTYH protein (p.Cys505Tyr). This variant is not present in population databases (gnomAD no frequency). 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: 419117). 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 | May 31, 2023 | This missense variant replaces cysteine with tyrosine at codon 505 of the MUTYH 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 not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified 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:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 25, 2023 | This missense variant replaces cysteine with tyrosine at codon 505 of the MUTYH 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 not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified 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 | Sep 01, 2023 | The p.C505Y variant (also known as c.1514G>A), located in coding exon 15 of the MUTYH gene, results from a G to A substitution at nucleotide position 1514. The cysteine at codon 505 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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 | May 26, 2015 | This variant is denoted MUTYH c.1514G>A at the cDNA level, p.Cys505Tyr (C505Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Cys505Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MUTYH Cys505Tyr occurs at a position that is not conserved and is not located in a known functional domain (Ruggieri 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MUTYH Cys505Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at