Submissions for variant NM_001048174.2(MUTYH):c.293G>A (p.Arg98Gln)

gnomAD frequency: 0.00001  dbSNP: rs587781444

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129359	SCV000184123	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The p.R126Q variant (also known as c.377G>A), located in coding exon 4 of the MUTYH gene, results from a G to A substitution at nucleotide position 377. The arginine at codon 126 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in two individuals with polyposis who were also heterozygous for an MUTYH mutation; however, phase was not confirmed in either individual (Guarinos C et al. Clin. Cancer Res. 2014 Mar;20:1158-68; Ambry internal data). This variant is designated as c.326G>A in Guarinos C et al. 2014. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460472	SCV000545783	uncertain significance	Familial adenomatous polyposis 2	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 126 of the MUTYH protein (p.Arg126Gln). This variant is present in population databases (rs587781444, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 141028). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731386	SCV000697686	uncertain significance	not specified	2021-09-11	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.377G>A (p.Arg126Gln), also known as c.326G>A (p.Arg109Gln), results in a conservative amino acid change in 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 2.8e-05 in 251354 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.377G>A has been reported in the literature in at-least one individual affected with MUTYH-Associated Polyposis (Guarinos_2014) and as a VUS in settings of multigene panel testing in one individual from a cohort of patients with familial pancreatic cancer (Takai_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
Color Diagnostics, LLC DBA Color Health	RCV000129359	SCV001357388	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001795250	SCV002032677	uncertain significance	not provided	2021-12-03	criteria provided, single submitter	clinical testing	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
Baylor Genetics	RCV000460472	SCV004198862	uncertain significance	Familial adenomatous polyposis 2	2023-09-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000460472	SCV005429864	uncertain significance	Familial adenomatous polyposis 2	2024-06-17	criteria provided, single submitter	clinical testing