Submissions for variant NM_001048174.2(MUTYH):c.1225C>T (p.Arg409Trp)

gnomAD frequency: 0.00003  dbSNP: rs587778540

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206561	SCV000260004	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 tryptophan, which is neutral and slightly polar, at codon 437 of the MUTYH protein (p.Arg437Trp). This variant is present in population databases (rs587778540, gnomAD 0.02%). This missense change has been observed in individual(s) with MUTYH-related conditins (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 134864). 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.
Ambry Genetics	RCV000214371	SCV000275427	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-24	criteria provided, single submitter	clinical testing	The p.R437W variant (also known as c.1309C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1309. The arginine at codon 437 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in a study of 1,165 individuals with a history of colorectal cancer or colon polyps as well as 590 controls (Gordon AS et al. Am J Hum Genet, 2019 09;105:526-533). This alteration was also identified in an individual diagnosed with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). This amino acid position is poorly 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.
Illumina Laboratory Services, Illumina	RCV000206561	SCV000357890	uncertain significance	Familial adenomatous polyposis 2	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000206561	SCV000487384	uncertain significance	Familial adenomatous polyposis 2	2016-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000590752	SCV000566268	uncertain significance	not provided	2021-08-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in a colorectal cancer/polyps case-control study, but it is unclear whether it was detected in cases or controls (Gordon 2019); This variant is associated with the following publications: (PMID: 23108399, 31422818, 28452373, 24728327)
Color Diagnostics, LLC DBA Color Health	RCV000214371	SCV000685565	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 437 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 not been reported in individuals affected with hereditary cancer in the literature but has been reported in a healthy individual (PMID: 24728327). This variant has been identified in 8/282742 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	RCV000590752	SCV000697675	uncertain significance	not provided	2016-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121597	SCV000731384	uncertain significance	not specified	2017-02-20	criteria provided, single submitter	clinical testing	The p.Arg437Trp variant in MUTYH has not been previously reported in individuals with MUTYH-associated polyposis but has been identified in 1/11568 of Latino ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs587778540). Although this variant has been seen in the general popu lation, its frequency is not high enough to rule out a pathogenic role. Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In summary, the clinical significance of the p.Arg437Trp variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590752	SCV000888307	uncertain significance	not provided	2017-11-02	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000206561	SCV003807029	uncertain significance	Familial adenomatous polyposis 2	2022-09-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated, BP4 supporting
Baylor Genetics	RCV000206561	SCV004198856	uncertain significance	Familial adenomatous polyposis 2	2023-09-26	criteria provided, single submitter	clinical testing
ITMI	RCV000121597	SCV000085794	not provided	not specified	2013-09-19	no assertion provided	reference population