ClinVar Genomic variation as it relates to human health

Variant summary: MUTYH c.649C>T (p.Arg217Cys) results in a non-conservative amino acid change located in the HhH-GPD_domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This frequency is lower than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (4.9e-05 vs 0.0046), allowing no conclusion about variant significance. The c.649C>T has been reported in the literature in individuals affected with multiple colorectal adenomas. These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least one individual with a personal history of colon cancer who underwent multi-gene panel testing (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 17949294, 33471991, 28135145)

This missense variant replaces arginine with cysteine at codon 217 of the MUTYH protein. This variant is also known as NM_001048171.1:c.607C>T (p.Arg203Cys) and NM_001048174.2:c.565C>T (p.Arg189Cys) in the literature. 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 reported for this variant. This variant has been reported in an individual affected with colorectal cancer and in an individual affected with polyposis (PMID: 17949294, 28135145). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and 4/53461 controls (OR=0.663, 95%CI 0.148 to 2.963, p-value=0.713; PMID: 33471991). This variant has been identified in 12/251394 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 cysteine at codon 217 of the MUTYH protein. This variant is also known as NM_001048171.1:c.607C>T (p.Arg203Cys) and NM_001048174.2:c.565C>T (p.Arg189Cys) in the literature. 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 reported for this variant. This variant has been reported in an individual affected with colorectal cancer and in an individual affected with polyposis (PMID: 17949294, 28135145). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and 4/53461 controls (OR=0.663, 95%CI 0.148 to 2.963, p-value=0.713; PMID: 33471991). This variant has been identified in 12/251394 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.R217C variant (also known as c.649C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 649. The arginine at codon 217 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in an individual diagnosed with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This variant was also reported in 3/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 217 of the MUTYH protein (p.Arg217Cys). This variant is present in population databases (rs537292657, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MUTYH related conditions (PMID: 17949294, 28135145; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.607C>T (p.Arg203Cys) and c.565C>T (p.Arg189Cys). ClinVar contains an entry for this variant (Variation ID: 184447). 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.