Submissions for variant NM_001048174.2(MUTYH):c.1392+2C>T

gnomAD frequency: 0.00031  dbSNP: rs140288388

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166725	SCV000217536	benign	Hereditary cancer-predisposing syndrome	2019-10-11	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470920	SCV000545716	likely benign	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506630	SCV000601636	uncertain significance	not specified	2017-05-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166725	SCV000685586	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide substitution at the +2 position of intron 14 of the MUTYH gene. 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. This variant has been identified in 37/282888 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	RCV000506630	SCV000697679	uncertain significance	not specified	2021-07-18	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1476+2C>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 5/5 computational tools predict that this variant strengthens the canonical 5' splicing donor site (i.e. it seems to change a non-classical splice site into a classic, consensus splice site), therefore no significant impact on normal splicing is expected. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251488 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0012 in the gnomAD database. This frequency is not higher than the expected maximum for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.0046), allowing no conclusion about variant significance. c.1476+2C>T has been reported in the literature as a VUS in 2 individuals affected with breast cancer undergoing multigene panel testing (example, Tung_2014). This report does not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=6), or benign (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as Variant of Uncertain Significance (VUS).
Counsyl	RCV000470920	SCV000797044	uncertain significance	Familial adenomatous polyposis 2	2018-01-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000470920	SCV000914411	uncertain significance	Familial adenomatous polyposis 2	2017-05-28	criteria provided, single submitter	clinical testing	The MUTYH c.1434+2C>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for MYH-associated polyposis.
Mendelics	RCV000470920	SCV001135248	uncertain significance	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001358548	SCV001866249	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166725	SCV002532243	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000506630	SCV004024353	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000470920	SCV004236652	uncertain significance	Familial adenomatous polyposis 2	2023-06-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000470920	SCV004817134	uncertain significance	Familial adenomatous polyposis 2	2024-02-05	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide substitution at the +2 position of intron 14 of the MUTYH gene. 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. This variant has been identified in 37/282888 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358548	SCV001554315	uncertain significance	not provided		no assertion criteria provided	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000470920	SCV004807342	likely pathogenic	Familial adenomatous polyposis 2	2024-03-26	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739539	SCV005361611	uncertain significance	MUTYH-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The MUTYH c.1476+2C>T variant is predicted to interfere with splicing. This variant is predicted to restore the donor splice site in intron 14 to a consensus splice site (GT) based on available splicing prediction programs (Alamut v2.11). This variant was reported as uncertain significance in two individuals with breast cancer (see Cohort 1 and Cohort 2 in Supporting Data; Tung et al. 2015. PubMed ID: 25186627). This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD, and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/187040/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.