Submissions for variant NM_001048174.2(MUTYH):c.461G>T (p.Arg154Leu)

gnomAD frequency: 0.00006  dbSNP: rs143353451

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164867	SCV000215551	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	The p.R182L variant (also known as c.545G>T), located in coding exon 7 of the MUTYH gene, results from a G to T substitution at nucleotide position 545. The arginine at codon 182 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in conjunction with two different MUTYH pathogenic variants in individuals diagnosed with clinical features of MUTYH -associated disease. In one case, this alteration was identified as likely in trans with the second MUTYH variant, and in the second case, the phase of the two variants is unknown (Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164867	SCV000685640	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 182 of the MUTYH protein. This variant is also known as c.503G>T (p.Arg168Leu) 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 reported for this variant. However, two other missense variants at this codon have been reported as loss-of-function in mutation suppressive activity and in vitro glycosylase activity assays (PMID: 20848659, 23322991). This variant has not been reported in individuals affected with hereditary cancer in the literature. Two different missense variants at the same codon, p.Arg182Cys and p.Arg182His, are reported as disease-causing in ClinVar (variation ID: 182689, 187280). These two other missense variants have been reported in heterozygosity with a second pathogenic MUTYH variant in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 15366000, 16207212, 16557584, 16890597, 19394335, 20618354). This variant has been identified in 3/282842 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799235	SCV000938889	likely pathogenic	Familial adenomatous polyposis 2	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 182 of the MUTYH protein (p.Arg182Leu). This variant is present in population databases (rs143353451, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis (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: 185441). 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. This variant disrupts the p.Arg182 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15236166, 16890597, 18091433, 18301448, 19279422, 20848659, 23322991, 25820570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV001770127	SCV002003231	likely pathogenic	not provided	2023-07-11	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320581	SCV004025067	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000799235	SCV004837390	uncertain significance	Familial adenomatous polyposis 2	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 182 of the MUTYH protein. This variant is also known as c.503G>T (p.Arg168Leu) 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 reported for this variant. However, two other missense variants at this codon have been reported as loss-of-function in mutation suppressive activity and in vitro glycosylase activity assays (PMID: 20848659, 23322991). This variant has not been reported in individuals affected with hereditary cancer in the literature. Two different missense variants at the same codon, p.Arg182Cys and p.Arg182His, are reported as disease-causing in ClinVar (variation ID: 182689, 187280). These two other missense variants have been reported in heterozygosity with a second pathogenic MUTYH variant in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 15366000, 16207212, 16557584, 16890597, 19394335, 20618354). This variant has been identified in 3/282842 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.
Baylor Genetics	RCV000799235	SCV005056088	uncertain significance	Familial adenomatous polyposis 2	2023-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003320581	SCV005380974	uncertain significance	not specified	2024-08-16	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.545G>T (p.Arg182Leu) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.545G>T has been reported in the literature in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating an impact on protein function has been reported. Different variants affecting the same codon have been classified as pathogenic by our lab (c.544C>T, p.Arg182Cys and c.545G>A, p.Arg182His), supporting the critical relevance of codon 182 to MUTYH protein function. ClinVar contains an entry for this variant (Variation ID: 185441). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.