rs587781864
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_001048174.2(MUTYH):c.464G>A(p.Gly155Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,076 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G155S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001048174.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.548G>A | p.Gly183Asp | missense_variant | 7/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.464G>A | p.Gly155Asp | missense_variant | 7/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.548G>A | p.Gly183Asp | missense_variant | 7/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.464G>A | p.Gly155Asp | missense_variant | 7/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251458Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461886Hom.: 0 Cov.: 36 AF XY: 0.0000138 AC XY: 10AN XY: 727246
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 183 of the MUTYH protein (p.Gly183Asp). This variant is present in population databases (rs587781864, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis in the homozygous or compound heterozygous states (PMID: 20223003; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 141595). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 15, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces glycine with aspartic acid at codon 183 of the MUTYH protein. This variant is also known as c.506G>A (p.Gly169Asp) based on an alternative transcript (NM_001048171). 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 performed for this variant. This variant has been reported in two siblings who have an in-trans pathogenic MUTYH variant and are affected with familial polyposis (PMID: 20223003) as well as an individual carrying a second pathogenic variant in MUTYH and affected with colorectal polyposis (DOI: 10.33878/2073-7556-2022-21-2-58-63 ). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 04, 2019 | - - |
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 28, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MUTYH p.Gly183Asp variant was identified in literature in 1 out of 90 Polish patients with familial polyposis and negative for an APC mutation (Skrzypczak 2006). In this reported case, the p.Tyr179Cys was also identified on the other allele; however, the pathogenicity of the p.Gly183Asp variant could not be determined with certainty. This variant was not reported in the HGMD, COSMIC, InSiGHT or LOVD databases. The p.Gly183 residue is conserved in mammals but not in Fission yeast; and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. This variant is not predicted to affect normal splicing. In summary, based on the above information the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 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; Also known as c.506G>A, p.Gly169Asp; This variant is associated with the following publications: (PMID: 20223003) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2023 | This missense variant replaces glycine with aspartic acid at codon 183 of the MUTYH protein. This variant is also known as c.506G>A (p.Gly169Asp) based on an alternative transcript (NM_001048171). 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 performed for this variant. This variant has been reported in two siblings who have an in-trans pathogenic MUTYH variant and are affected with familial polyposis (PMID: 20223003) as well as an individual carrying a second pathogenic variant in MUTYH and affected with colorectal polyposis (DOI: 10.33878/2073-7556-2022-21-2-58-63 ). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2022 | The p.G183D pathogenic mutation (also known as c.548G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 548. The glycine at codon 183 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in conjunction with another pathogenic MUTYH mutation in two brothers with polyposis (Skrzypczak M et al. Hered. Cancer Clin. Pract. 2006;4:43-7). In addition, this alteration has been identified in several individuals with a second known MUTYH mutation in trans and a personal and family history consistent with MUTYH-associated polyposis (MAP) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at