ClinVar Genomic variation as it relates to human health

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.

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.

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)

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.

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.

The MUTYH c.548G>A (p.Gly183Asp) variant has been reported in the published literature in-trans with another pathogenic MUTYH variant in an individual with familial adenomatous polyposis (PMID: 20223003 (2006)). In addition, this variant has been reported in-trans with a second MUTYH variant in individuals with a personal and family history of MUTYH-associated polyposis (personal communication with Ambry Genetics related to Clinvar ID: 141595). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

The MUTYH p.Gly183Asp variant was identified in 1 of 180 proband chromosomes (frequency: 0.006) from Polish individuals or families with FAP (Skrzypczak 2006). In this study the proband was affected with familial polyposis but negative for an APC pathogenic variant, and the variant co-occurred in trans with a pathogenic MUTYH variant (494A>G, Y165C). Similar observations have been made by our laboratory in two individuals both with MUTYH-related disease and with co-occurring MUTYH pathogenic variants (c.536A>G, p.Tyr179Cys and c.1187G>A, p.Gly396Asp) however phase was not determined. In discussion with additional clinical laboratories we identified multiple affected patients with this variant and a co-occurring pathogenic MUTYH variant, although phase was generally undetermined there was one case where phase was determined to be trans. The variant was also identified in dbSNP (ID: rs587781864) as “With Likely pathogenic” allele, and in ClinVar (classified with conflicting interpretations of pathogenicity; submitters: pathogenic by Ambry Genetics, likely pathogenic by GeneDx and Color, and uncertain significance by Invitae). The variant was identified in control databases in 1 of 246272 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), observed in the following population: Finnish in 1 of 22300 chromosomes (freq: 0.00005) while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian and South Asian populations. The p.Gly183 residue is conserved in mammals and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) predict that the variant will impact the function of the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.