Submissions for variant NM_001048174.2(MUTYH):c.488G>A (p.Arg163Gln)

gnomAD frequency: 0.00006  dbSNP: rs369677603

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212702	SCV000149677	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer study (Dorling et al., 2021); Observed in an individual who underwent multigene panel testing due to unspecified familial cancer (Tsaousis et al., 2019); This variant is associated with the following publications: (PMID: 33471991, 31159747)
Ambry Genetics	RCV000115768	SCV000183833	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-25	criteria provided, single submitter	clinical testing	The p.R191Q variant (also known as c.572G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 572. The arginine at codon 191 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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	RCV000168022	SCV000218674	uncertain significance	Familial adenomatous polyposis 2	2024-01-29	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 191 of the MUTYH protein (p.Arg191Gln). This variant is present in population databases (rs369677603, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 127846). 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	RCV000168022	SCV000799307	uncertain significance	Familial adenomatous polyposis 2	2018-04-09	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115768	SCV000822075	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212702	SCV000888319	uncertain significance	not provided	2018-05-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765176	SCV000896409	uncertain significance	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115768	SCV000902721	likely benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192928	SCV001361389	uncertain significance	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.572G>A (p.Arg191Gln) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of 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 6.4e-05 in 251474 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (6.4e-05 vs 0.0046), allowing no conclusion about variant significance. c.572G>A has been reported in the literature in a cohort of individuals under going genetic testing (exact phenotype of the reported individual was not provided)(Tsaousis_2019). This report does not provide an unequivocal conclusion about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant seven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000115768	SCV002532302	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192928	SCV004025045	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000168022	SCV004198805	uncertain significance	Familial adenomatous polyposis 2	2023-10-22	criteria provided, single submitter	clinical testing