Submissions for variant NM_001048174.2(MUTYH):c.900C>T (p.Asp300=)

gnomAD frequency: 0.00003  dbSNP: rs587780752

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123159	SCV000166464	likely benign	Familial adenomatous polyposis 2	2024-12-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000123159	SCV000487357	likely benign	Familial adenomatous polyposis 2	2016-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000757499	SCV000525024	likely benign	not provided	2019-05-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567348	SCV000666455	likely benign	Hereditary cancer-predisposing syndrome	2015-10-11	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.
Color Diagnostics, LLC DBA Color Health	RCV000567348	SCV000685683	likely benign	Hereditary cancer-predisposing syndrome	2017-04-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757499	SCV000885749	likely benign	not provided	2018-03-17	criteria provided, single submitter	clinical testing	The c.984C>T; p.Asp328Asp variant (rs587780752, ClinVar variant ID 135993) does not alter the amino acid sequence of the MUTYH protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site. This variant has not been reported in medical literature or in gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.001% (identified on 4 out of 277,162 chromosomes). Based on the available information, the c.984C>T variant is likely to be benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000441650	SCV001363479	likely benign	not specified	2020-01-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000441650	SCV002069471	likely benign	not specified	2018-08-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123159	SCV004835214	likely benign	Familial adenomatous polyposis 2	2023-11-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000123159	SCV001551753	likely benign	Familial adenomatous polyposis 2		no assertion criteria provided	clinical testing	The MUTYH p.Asp328= variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs587780752) as "With Likely benign, Uncertain significance allele", and in ClinVar (classified as likely benign by Invitae, Counsyl, GeneDx, Ambry Genetics and Color Genomics). The variant was identified in control databases in 4 of 277162 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 126666 chromosomes (freq: 0.00002), and South Asian in 2 of 30782 chromosomes (freq: 0.00007); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Asp328 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.