ClinVar Genomic variation as it relates to human health

The p.Gly503Glu variant in MUTYH has been reported in one individual with clinic al features of Lynch Syndrome as well as in one young reportedly healthy individ ual (Bodian 2014). This variant has also been reported by other clinical laborat ories in Clinvar (Variation ID: 134866) and has been identified in 0.22% (51/231 22) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs3219494). Although this variant has been seen i n the general population, its frequency is not high enough to rule out a pathoge nic role. In vitro functional studies provide some evidence that the p.Gly503Glu variant may impact protein function (Komine 2015). Additionally, computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Gly503Glu variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25186627 (2015), 32868316 (2020), 35264596 (2022)), suspected Lynch syndrome (PMID: 25980754 (2015)), and endometrial cancer (PMID: 26689913 (2015)). A published functional study has shown that this variant displays partially defective base excision repair activity without affecting protein expression or localization (PMID: 25820570 (2015)). The frequency of this variant in the general population, 0.0023 (56/24032 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: MUTYH c.1508G>A (p.Gly503Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 243210 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00013 vs 0.0046), allowing no conclusion about variant significance. c.1508G>A has been reported in the literature in colorectal/breast cancer cases and in the TGCA cohort (e.g. Yurgelun_2015, Lu_2015, Tung_2015, Purrington_2020, Barreiro_2022, Guindalini_2022, de Oliveria_2022). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least one publication has reported experimental evidence evaluating an impact on protein function and found the variant caused a partial defect in an E.coli model system (Komine 2015). The following publications have been ascertained in the context of this evaluation (PMID: 34816434, 24728327, 35264596, 25820570, 26689913, 32868316, 25186627, 25980754, 35534704). ClinVar contains an entry for this variant (Variation ID: 134866). Based on the evidence outlined above, the variant was classified as uncertain significance.

The MUYTH c.1508G>A (p.Gly503Glu) missense variant has a maximum subpopulation frequency of 0.23% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function. This variant was found to cause partial loss of MUTYH function in a bacterial complementation assay (PMID: 25820570). This variant has been reported in individuals with colorectal cancer and/or Lynch syndrome (PMID: 25980754, 28944238). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

The MUTYH c.1508G>A variant is predicted to result in the amino acid substitution p.Gly503Glu. This variant has been reported in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), in individuals with breast cancer (Supplementary Table, Tung et al. 2015. PubMed ID: 25186627; Table S3, Purrington et al. 2020. PubMed ID: 32868316), and in individuals from a healthy, ancestrally diverse genome sequencing cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). Functional studies also suggest this variant impacts base excision repair activity of the MUTYH protein (Komine et al. 2015. PubMed ID: 25820570). This variant is reported in 0.23% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45796198-C-T) and is interpreted as uncertain significant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134866/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 503 of the MUTYH protein (p.Gly503Glu). This variant is present in population databases (rs3219494, gnomAD 0.2%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 25980754, 26689913). This variant is also known as c.1466G>A. ClinVar contains an entry for this variant (Variation ID: 134866). 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. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570). 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.

In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies demonstrate partially defective base excision repair activity in a yeast-based complementation assay and reduced protein expression (PMID: 25820570); This variant is associated with the following publications: (PMID: 25186627, 25980754, 24728327, 21167187, 21153778, 26689913, 32868316, 30122538, 34816434, 35534704, 35264596, 25820570)

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This missense variant replaces glycine with glutamic acid at codon 503 of the MUTYH protein. This variant is also known as c.1466G>A (p.Gly489Glu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported this variant as causing partial loss of MUTYH function in a bacterial complementation assay (PMID: 25820570). This variant has been reported in an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 60/274602 chromosomes (56/24032 African 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.

This missense variant replaces glycine with glutamic acid at codon 503 of the MUTYH protein. This variant is also known as c.1466G>A (p.Gly489Glu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported this variant as causing partial loss of MUTYH function in an bacterial complementation assay (PMID: 25820570). This variant has been reported in an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 60/274602 chromosomes (56/24032 African 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.