Submissions for variant NM_001048174.2(MUTYH):c.228C>T (p.Tyr76=)

dbSNP: rs121908380

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119223	SCV000153967	benign	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000177119	SCV000170421	benign	not specified	2013-11-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000126890	SCV000212844	likely benign	Hereditary cancer-predisposing syndrome	2014-06-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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)	RCV000177119	SCV000228946	benign	not specified	2015-03-27	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000119223	SCV000297027	benign	Familial adenomatous polyposis 2	2015-12-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000177119	SCV000539814	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: ExAC: 0.5% Finnish chromosomes; ClinVar: 4 labs classify as LB/B
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513902	SCV000609577	likely benign	not provided	2017-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126890	SCV000685610	benign	Hereditary cancer-predisposing syndrome	2016-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000513902	SCV000697690	benign	not provided	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.312C>T (p.Tyr104Tyr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 161/124730 control chromosomes at a frequency of 0.0012908, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0055902). This variant has been reported in numerous patients with various types of cancer, however, without enough evidence suggesting pathogenicity. In one internal sample (91 y.o.), co-occurrence of this variant and BRIP1 c.484C>T (classified as likely pathogenic by LCA) was found, suggesting the variant of interest is unlikely to be pathogenic. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000513902	SCV000806353	likely benign	not provided	2017-07-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513902	SCV000888312	likely benign	not provided	2023-09-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513902	SCV001147273	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MUTYH: BP4, BP7
Illumina Laboratory Services, Illumina	RCV000119223	SCV001257410	uncertain significance	Familial adenomatous polyposis 2	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513902	SCV001473093	likely benign	not provided	2022-01-26	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000513902	SCV002011193	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000177119	SCV002067698	likely benign	not specified	2021-08-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126890	SCV002532275	likely benign	Hereditary cancer-predisposing syndrome	2021-07-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000177119	SCV002552524	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126890	SCV002819175	likely benign	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000119223	SCV004837909	benign	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353596	SCV000592678	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Tyr104= variant was identified in 6 of 8036 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, breast cancer, or adenomatous polyposis and was not identified in 3332 control chromosomes from healthy individuals (Out 2012, Aretz 2006, Alhopuro 2005, McVeigh 2016, Niessen 2006, Olschwang 2007). The variant was also identified in dbSNP (ID: rs121908380) as “With Pathogenic, other allele”, ClinVar (classified as benign by Invitae, GeneDx, Color Genomics and 4 clinical laboratories; as likely benign by Ambry Genetics and 3 clinical laboratories), Clinvitae, and COGR database. The variant was not identified in Cosmic, or UMD-LSDB databases. The variant was identified in control databases in 417 of 277196 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 13 of 24020 chromosomes (freq: 0.001), Other in 16 of 6464 chromosomes (freq: 0.002), Latino in 50 of 34420 chromosomes (freq: 0.001), European in 213 of 126700 chromosomes (freq: 0.002), East Asian in 1 of 18870 chromosomes (freq: 0.0001), Finnish in 123 of 25788 chromosomes (freq: 0.01), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish populations. The p.Tyr104= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
True Health Diagnostics	RCV000126890	SCV000788068	likely benign	Hereditary cancer-predisposing syndrome	2017-11-17	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000513902	SCV001739561	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000513902	SCV001809358	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000513902	SCV001919001	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513902	SCV001959459	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513902	SCV001974213	likely benign	not provided		no assertion criteria provided	clinical testing