Submissions for variant NM_001048174.2(MUTYH):c.1347G>C (p.Thr449=)

gnomAD frequency: 0.00596  dbSNP: rs74318065

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162570	SCV000212986	benign	Hereditary cancer-predisposing syndrome	2014-12-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000174706	SCV000226060	benign	not specified	2014-08-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000174706	SCV000539813	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, high frequency
Invitae	RCV001083142	SCV000557584	benign	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162570	SCV000685576	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000174706	SCV000806343	benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000174706	SCV000889520	benign	not specified	2020-08-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759880	SCV001159237	benign	not provided	2023-04-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759880	SCV001248076	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MUTYH: BP4, BP7, BS1, BS2
Illumina Laboratory Services, Illumina	RCV001083142	SCV001253573	likely benign	Familial adenomatous polyposis 2	2018-02-09	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000759880	SCV001836968	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27829682, 27884173, 16774938, 20981092)
Sema4, Sema4	RCV000162570	SCV002532237	benign	Hereditary cancer-predisposing syndrome	2020-08-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000174706	SCV002547277	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498804	SCV002795890	benign	Familial adenomatous polyposis 2; Gastric cancer	2022-03-17	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162570	SCV004014952	benign	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353747	SCV000592717	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Thr477Thr (c.1431G>C ) variant (alias 1389G>C) has been previously reported in the literature in 14/332 proband chromosomes (frequency 0.048) in individuals affected with either adenomatous polyposis, gastric cancer or colorectal cancer, however controls were not included in these studies (Peterlongo 2006, Tao 2004, Yanaru-Fujisawa 2008). This variant has also been identified in the HGMD and LOVD databases, however it is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, and has been reported in dbSNP (ID#:rs74318065), by the 1000 genomes project (frequency 0.016), and ESP project (frequency 0.004). However, there is some conflicting information in the literature. In one study the variant c.1431G > C was found to be in complete linkage disequilibrium with two other MUTYH variants, –280G > A and c.36+11C>T (alias IVS1+11C>T). A statistically significant association was demonstrated between one of these variants, c.36+11C>T and increased CRC risk (Tao 2008). This indicates that individuals with the MUTYH – 280A/c.36+11T/c.1431C genotypes may be susceptible to CRC (Tao 2008). However, replication in additional cohorts and additional functional evidence would be required to validate this finding. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as a variant of unknown significance (VUS).
True Health Diagnostics	RCV000162570	SCV000788064	likely benign	Hereditary cancer-predisposing syndrome	2017-06-21	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000759880	SCV001800318	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000174706	SCV001807696	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000759880	SCV001921567	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000759880	SCV001960022	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000174706	SCV001964337	benign	not specified		no assertion criteria provided	clinical testing