Submissions for variant NM_001048174.2(MUTYH):c.14G>A (p.Arg5Gln)

gnomAD frequency: 0.00003  dbSNP: rs587780081

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212697	SCV000149661	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21777424, 22297469, 25980754, 26689913, 23108399, 35264596)
Ambry Genetics	RCV000115752	SCV000186396	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The p.R19Q variant (also known as c.56G>A), located in coding exon 2 of the MUTYH gene, results from a G to A substitution at nucleotide position 56. The arginine at codon 19 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was reported in a patient with breast cancer, diagnosed at less than 55 years of age, and this alteration was classified by the authors as a variant of unknown significance (Out AA et al. Breast Cancer Res Treat (2012) 134:219–227). This alteration was also observed in 1/182 individuals undergoing a 25-gene panel test for a clinical suspicion of Lynch syndrome (Yurgelun MB et al. Gastroenterology. 2015 May 13) and in 1/62 individuals with colorectal cancer and/or colon polyps who were tested for MUTYH mutations (Tricarico R et al. BMC Cancer, 2011 Jul;11:305). This amino acid position is 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.
Invitae	RCV000230254	SCV000285958	uncertain significance	Familial adenomatous polyposis 2	2024-01-16	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 19 of the MUTYH protein (p.Arg19Gln). This variant is present in population databases (rs587780081, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer, suspected of Lynch syndrome and undergoing MUTYH-associated polyposis testing (PMID: 21777424, 22297469, 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 127834). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Counsyl	RCV000230254	SCV000790004	uncertain significance	Familial adenomatous polyposis 2	2017-03-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000230254	SCV000837785	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115752	SCV000911086	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 19 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754, 21777424) and in an individual affected with breast cancer (PMID: 22297469). This variant has been identified in 7/251490 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194162	SCV001363472	uncertain significance	not specified	2019-12-31	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.56G>A (p.Arg19Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.56G>A has been reported in the literature in at-least one individual undergoing clinical genetic testing for Lynch syndrome (Yurgelun_2015) and at-least one individual with breast cancer (Out_2012). These report(s) 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. Six 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.
Sema4, Sema4	RCV000115752	SCV002532299	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001194162	SCV004025112	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing