ClinVar Genomic variation as it relates to human health

Variant summary: MUTYH c.650G>A (p.Arg217His) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 282760 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (3.9e-05 vs 0.0046), allowing no conclusion about variant significance. c.650G>A has been reported in the literature in at least one compound heterozygous individual affected with MUTYH-Associated Polyposis (Thomas_2021). It has also been observed in individuals with colorectal adenomas (e.g. Olschwang_2007 and Schulz_2014) and breast cancer (e.g. Dorling_2021, Pereira_2022, Guindalini_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.650G>A, in exon 8 that results in an amino acid change, p.Arg217His. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the African/African American subpopulation (dbSNP rs147754007). The p.Arg217His change affects a highly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg217His substitution. This sequence change does not appear to have been previously described in individuals with MUTYH-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg217His change remains unknown at this time. ;

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 217 of the MUTYH protein (p.Arg217His). This variant is present in population databases (rs147754007, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal adenomas and/or colorectal cancer (PMID: 17949294, 25307848, 33130102, 34326862). ClinVar contains an entry for this variant (Variation ID: 140830). 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.

Observed in individuals with adenomatous polyps, colorectal cancer, and other cancers (Olschwang 2007, Schulz 2014, Schrader 2016); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.608G>A (p.Arg203His); This variant is associated with the following publications: (PMID: 17949294, 25307848, 26556299, 28873162)

This missense variant replaces arginine with histidine at codon 217 of the MUTYH protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the compound heterozygous state in an individual affected with MUTYH-associated polyposis (PMID: 33130102). This variant has also been reported in an individual affected with colorectal adenomas (PMID 17949294), a family with familial colorectal cancer (however, the variant did not segregate with the disease; PMID 25307848), an individual with unspecified cancer (PMID: 26556299), individuals affected with breast cancer, and healthy controls (PMID: 33471991, 35980532; DOI: 10.3390/biomedicines11051386). This variant has been identified in 11/282760 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 arginine with histidine at codon 217 of the MUTYH protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the compound heterozygous state in an individual affected with MUTYH-associated polyposis (PMID: 33130102). This variant has also been reported in an individual affected with colorectal adenomas (PMID 17949294), a family with familial colorectal cancer (however, the variant did not segregate with the disease; PMID 25307848), an individual with unspecified cancer (PMID: 26556299), individuals affected with breast cancer and healthy controls (PMID: 33471991). This variant has been identified in 11/282760 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.

The p.R217H variant (also known as c.650G>A), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 650. The arginine at codon 217 is replaced by histidine, an amino acid with highly similar properties. This alteration, designated as p.Arg203His, has been reported as a variant of unknown significance in an adenomatous polyposis cohort (Olschwang S et al. Genet. Test. 2007;11:315-20). In a different study, this alteration was detected in a large Austrian kindred with familial colorectal cancer type X (FCCTX) in conjunction with a SEMA4A gene alteration; this alteration did not segregate with colorectal cancer in the family whereas the SEMA4A gene alteration did (Schulz E et al. Nat Commun. 2014 Oct 13;5:5191). In addition, this alteration was detected in the germline of an individual with advanced cancer who underwent tumor-normal sequencing; although clinical details were not provided, authors noted that the patient's phenotypic expression was not consistent with an autosomal recessive mode of inheritance (Schrader KA et al. JAMA Oncol. 2016 Jan;2(1):104-11). This amino acid position is 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.

The MUTYH p.Arg217His variant was identified in APC-negative patients with more than 5 colorectal adenomas; the frequency of the variant in this cohort, zygosity and disease severity were not provided from this cohort (Olschwang 2007). It was also identified in a large Austrian kindred with Familial colorectal cancer type X (FCCTX), being studied for novel candidate gene mutations; but was excluded as the cause of neoplasms in this family due to non-segregation amongst family members (Schulz 2014). The variant was also identified in dbSNP (ID: rs147754007) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), ClinVar database (classification uncertain significance by Ambry Genetics), UMD (2x with a ”unclassified variant” classification), NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001) and in 1 of 4406 African American alleles (frequency: 0.0002), and the Exome Aggregation Consortium database (March 14, 2016) in 5 of 121252 chromosomes (freq. 0.00004) in the following populations: Latino in 1 of 11572 chromosomes (freq. 00009), South Asian in 1 of 16512 chromosomes (freq. 0.00006), European (Non-Finnish) in 3 of 66638 chromosomes (freq. 0.00005), but was not seen in African, East Asian, Finnish, and Other populations, increasing the likelihood this could be a low frequency benign variant. The p.Arg217 residue is conserved across mammals and lower organisms, and three out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the His variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.