Submissions for variant NM_025077.4(TOE1):c.-45G>A

gnomAD frequency: 0.00299  dbSNP: rs2275602

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000126892	SCV000170423	benign	not specified	2014-02-28	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.
PreventionGenetics, part of Exact Sciences	RCV000126892	SCV000306737	benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579941	SCV000685614	benign	Hereditary cancer-predisposing syndrome	2016-05-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003103733	SCV001159238	benign	Pontocerebellar hypoplasia type 7	2023-04-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001097390	SCV001253668	uncertain significance	Familial adenomatous polyposis 2	2018-02-27	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001097390	SCV001728679	benign	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000126892	SCV002067709	benign	not specified	2020-05-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000126892	SCV002570182	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579941	SCV002615376	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353844	SCV000592671	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH c.36+11C>T variant was identified in 7 of 276 proband chromosomes (frequency: 0.04) from individuals or families with (Shinmura 2014,Tao 2004, Zhou 2005). The variant was also identified in dbSNP (ID: rs2275602) as "With other allele", in ClinVar (3x as Benign by GeneDx, Colour Genomics and Prevention Genetics), Insight Colon Cancer Gene Variant Database (4x), and in UMD-LSDB (2x as unclassified variant). The variant was also identified by our laboratory in 7 individuals including 6 with a clinical indication for hereditary colon cancer testing. The variant was not identified in GeneInsight-COGR, Cosmic, or MutDB databases. The variant was identified in control databases in 914 of 275438 chromosomes (11 homozygous) at a frequency of 0.003 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 2 of 23810 chromosomes (freq: 0.00008), Other in 17 of 6424 chromosomes (freq: 0.003), Latino in 3 of 34366 chromosomes (freq: 0.00009), European Non-Finnish in 133 of 125622 chromosomes (freq: 0.001), East Asian in 467 of 18808 chromosomes (freq: 0.02), Finnish in 213 of 25526 chromosomes (freq: 0.008), and South Asian in 79 of 30766 chromosomes (freq: 0.003), while the variant was not observed in the Ashkenazi Jewish population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing; however, the c.36+11C>T variant is located in the boundary region between MUTYH exon 1 and intron 1 and many reports have suggested that gene variants in the neighborhood of the junction are often accompanied by abnormal splicing (Tao 2008). In a Japanese population-based study, a statistically significant association was demonstrated between this variant and increased CRC risk (Tao 2008). Moreover, one haplotype containing the variant c.36+11T was demonstrated to be associated with increased CRC risk (OR of 1.43, haplotype .36+11C>T, c.504+35A>G, c.934−2A>G, and c.1014G>C, “TGAC”). The c.36+11C>T variant was found to be in complete linkage disequilibrium with two other MUTYH variants, –280G>A and c.1389G>C. These results indicate that individuals with the MUTYH – 280A/c.36+11T/c.1431C genotypes or the TGAC haplotype are susceptible to CRC (Tao 2008). 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573000	SCV001798247	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000126892	SCV001809044	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000126892	SCV001955783	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000126892	SCV001969905	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000126892	SCV001978830	benign	not specified		no assertion criteria provided	clinical testing