Submissions for variant NM_001048174.2(MUTYH):c.-6-5T>G

dbSNP: rs876660715

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219910	SCV000278357	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	The c.37-5T>G intronic variant results from a T to G substitution 5 nucleotides upstream from coding exon 2 in the MUTYH gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000481124	SCV000567285	uncertain significance	not provided	2016-04-28	criteria provided, single submitter	clinical testing	This variant is denoted MUTYH c.37-5T>G or IVS1-5T>G and consists of a T>G nucleotide substitution at the -5 position of intron 1 of the MUTYH gene. Multiple in silico models predict this variant to damage the nearby natural acceptor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH c.37-5T>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The thymine (T) nucleotide that is altered is conserved through mammals. Based on currently available information, it is unclear whether MUTYH c.37-5T>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547282	SCV000639316	likely benign	Familial adenomatous polyposis 2	2024-10-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219910	SCV000911621	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the -5 position of intron 1 of the MUTYH gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified 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	RCV001192931	SCV001361393	uncertain significance	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.37-5T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.37-5T>G in individuals affected with MUTYH-associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6952C>T, p.Arg2318X; internal sample). Four ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000547282	SCV004824331	uncertain significance	Familial adenomatous polyposis 2	2023-12-01	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the -5 position of intron 1 of the MUTYH gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified 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.