Submissions for variant NM_001048174.2(MUTYH):c.467G>A (p.Arg156Gln)

gnomAD frequency: 0.00001  dbSNP: rs758567247

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167475	SCV000218332	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The p.R184Q variant (also known as c.551G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 551. The arginine at codon 184 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in one Korean individual with seven colorectal polyps and was not detected in 300 controls (Kim JC et al. Virchows Arch. 2007 Mar;450(3):311-9). This alteration was also detected in 1/299 Italian patients who underwent clinical testing for multiple adenomatous polyposis (Ricci MT et al. J. Hum. Genet. 2017 Feb;62(2):309-315). Of note, this alteration is also known as p.R170Q in published literature. 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.
GeneDx	RCV000482615	SCV000568582	uncertain significance	not provided	2020-04-29	criteria provided, single submitter	clinical testing	Observed in individuals with a personal history of colorectal cancer and/or polyps (Kim 2007, Ricci 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Arg170Gln or p.Arg181Gln; This variant is associated with the following publications: (PMID: 17252231, 27829682)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557996	SCV000639340	uncertain significance	Familial adenomatous polyposis 2	2024-01-27	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 184 of the MUTYH protein (p.Arg184Gln). This variant is present in population databases (rs758567247, gnomAD 0.03%). This missense change has been observed in individual(s) with multiple colorectal adenomas and MUTYH-associated polyposis (PMID: 17252231, 27829682). This variant is also known as MYH R170Q. ClinVar contains an entry for this variant (Variation ID: 187723). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Color Diagnostics, LLC DBA Color Health	RCV000167475	SCV000685641	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 184 of the MUTYH protein. 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 performed for this variant. This variant has been reported in individuals affected with multiple colorectal adenomas or colorectal cancer (PMID: 17252231, 27829682) and metastatic pancreatic adenocarcinoma (PMID: 36135357). This variant has been identified in 5/282822 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.
Counsyl	RCV000557996	SCV000789004	uncertain significance	Familial adenomatous polyposis 2	2016-12-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482615	SCV002047024	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00029 (3/10370 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with colorectal cancer and colorectal polyps (PMIDs: 27829682 (2016) and 17252231 (2007)). It has also been reported in individuals with breast and/or ovarian cancer (PMID: 32068069 (2020), as well as in a breast cancer case and control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000167475	SCV002532297	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000557996	SCV004837356	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 184 of the MUTYH protein. 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 performed for this variant. This variant has been reported in individuals affected with multiple colorectal adenomas or colorectal cancer (PMID: 17252231, 27829682) and metastatic pancreatic adenocarcinoma (PMID: 36135357). This variant has been identified in 5/282822 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.