Submissions for variant NM_001048174.2(MUTYH):c.493-5A>G

gnomAD frequency: 0.00001  dbSNP: rs758377868

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162459	SCV000212816	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	The c.577-5A>G intronic pathogenic mutation results from an A to G substitution 5 nucleotides upstream from coding exon 8 in the MUTYH gene. This variant has been identified in conjunction with pathogenic MUTYH mutations in probands with adenomatous polyposis (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. In a study involving RNA extraction for RT-PCR and Sanger sequencing of 10 hereditary cancer genes, incomplete disruption of the natural splice site was observed for this alteration (Rofes P et al. J Mol Diagn. 2020 12;22:1453-1468). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000180208	SCV000232602	uncertain significance	not provided	2015-01-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000411665	SCV000487365	uncertain significance	Familial adenomatous polyposis 2	2016-06-15	criteria provided, single submitter	clinical testing
Invitae	RCV000411665	SCV000545740	pathogenic	Familial adenomatous polyposis 2	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs758377868, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 10612827, 21520333, 32133419, 33011440; Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 183746). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 32133419, 33011440; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162459	SCV000685648	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -5 position of intron 7 of the MUTYH gene. Functional RNA studies have shown that this variant causes aberrant splicing and results in a partial retention of intron 7 (r.576_577ins577-4_577-1), which is predicted to cause a frameshift and premature protein truncation (PMID: 32133419, 33011440). This variant has been observed in the homozygous state and compound heterozygous state in multiple individuals affected with severe polyposis (PMID: 32133419, 33011440, 34704405). This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Mendelics	RCV000411665	SCV000837772	uncertain significance	Familial adenomatous polyposis 2	2023-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411665	SCV001774639	pathogenic	Familial adenomatous polyposis 2	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.577-5A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 3 acceptor site. Two predict the variant weakens a 3 acceptor site. Two predict the variant creates a 3 cryptic acceptor site. Additionally, at least two RNA studies report this variant causes aberrant splicing and shows the inclusion of the last four nucleotides of intron 7 [r.576_577ins(577-4_577-1)], which presumably would generate a truncated protein (p.Val165Serfs*61) (Landrith_2020, Rofes_2020). The variant allele was found at a frequency of 4e-06 in 252164 control chromosomes (gnomAD and publication data). c.577-5A>G has been reported in the literature in two individuals affected with severe polyposis and one homozygous individual with personal and family records of colorectal polyps (Landrith_2020, Rofes_2020). These data indicate that the variant is likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3), likely pathogenic (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000180208	SCV001779816	pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate aberrant splicing (Rofes et al., 2020; Landrith et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33011440, 34704405, 35668106, 32133419)