Submissions for variant NM_001048174.2(MUTYH):c.1380C>T (p.Thr460=)

gnomAD frequency: 0.00001  dbSNP: rs373973053

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163503	SCV000214061	likely benign	Hereditary cancer-predisposing syndrome	2015-06-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225914	SCV000285931	likely benign	Familial adenomatous polyposis 2	2024-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001721046	SCV000513738	likely benign	not provided	2019-06-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163503	SCV000685583	likely benign	Hereditary cancer-predisposing syndrome	2016-11-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423962	SCV001337803	likely benign	not specified	2020-01-22	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000225914	SCV004016031	likely benign	Familial adenomatous polyposis 2	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000423962	SCV004024912	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000225914	SCV004831757	likely benign	Familial adenomatous polyposis 2	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355953	SCV001550986	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Thr488= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, or UMD-LSDB, databases. The variant was identified in dbSNP (ID: rs373973053) as "With Likely benign allele ", and in ClinVar database (classified as likely benign by Ambry Genetics, Invitae, GeneDx, and Color Genomics). The variant was identified in control databases in 5 of 246234 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 3 of 33582 chromosomes (freq: 0.00009), European in 1 of 111694 chromosomes (freq: 0.000009), East Asian in 1 of 17248 chromosomes (freq: 0.00006), while the variant was not observed in the African, Other, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Thr488= 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.