ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.475C>A (p.Leu159Met) (rs199862273)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215207 SCV000277285 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing The p.L159M variant (also known as c.475C>A), located in coding exon 6 of the MUTYH gene, results from a C to A substitution at nucleotide position 475. The leucine at codon 159 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000766675 SCV000293286 uncertain significance not provided 2015-10-26 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.475C>A at the cDNA level, p.Leu159Met (L159M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Leu159Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MUTYH Leu159Met occurs at a position that is conserved in mammals and is not located in a known functional domain (Ruggieri 2013, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MUTYH Leu159Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Invitae RCV000554382 SCV000639328 uncertain significance MYH-associated polyposis 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 159 of the MUTYH protein (p.Leu159Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 232997). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000766675 SCV000592684 uncertain significance not provided no assertion criteria provided clinical testing The MUTYH p.Leu159Met variant was not reported in the literature, nor was it reported in the HGMD, COSMIC, InSiGHT or LOVD databases. The p.Leu159 residue is conserved in some but not all mammals; and computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. This variant is located outside of the consensus sequence and, based on computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder), 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.

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