Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genomic Medicine Center of Excellence, |
RCV000411665 | SCV006553127 | pathogenic | Familial adenomatous polyposis 2 | 2025-09-10 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV000411665 | SCV005919636 | uncertain significance | Familial adenomatous polyposis 2 | 2019-11-01 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000411665 | SCV005429853 | pathogenic | Familial adenomatous polyposis 2 | 2024-07-29 | 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. |
| Baylor Genetics | RCV000411665 | SCV005056097 | likely pathogenic | Familial adenomatous polyposis 2 | 2023-11-03 | criteria provided, single submitter | clinical testing | |
| Gene |
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) |
| Women's Health and Genetics/Laboratory Corporation of America, |
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. |
| Mendelics | RCV000411665 | SCV000837772 | likely pathogenic | Familial adenomatous polyposis 2 | 2025-02-05 | criteria provided, single submitter | clinical testing | The c.493-5A>G (NM_001048174.2) intronic variant results from an A to G substitution 5 nucleotides upstream from coding exon 8 in the MUTYH gene. It has been previously reported in the homozygous state and/or compound heterozygous state in individuals with clinical characteristics of MUTYH-associated polyposis (PMID: 32133419, 33011440, 34704405). In silico analysis predicts that this alteration will weaken the native splice site. Functional RNA studies have shown that this variant causes abnormal splicing and results in an inclusion of 4bp (PMID: 32133419, 33011440). Therefore the available evidence suggests that this variant is likely to be pathogenic. |
| Color Diagnostics, |
RCV000162459 | SCV000685648 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-03-14 | 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 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. |
| Labcorp Genetics |
RCV000411665 | SCV000545740 | pathogenic | Familial adenomatous polyposis 2 | 2026-01-24 | 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 altered 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; external communication, internal data). 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 32133419, 33011440; internal data). For these reasons, this variant has been classified as Pathogenic. |
| Eurofins Ntd Llc |
RCV000180208 | SCV000232602 | uncertain significance | not provided | 2015-01-12 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000162459 | SCV000212816 | pathogenic | Hereditary cancer-predisposing syndrome | 2025-07-01 | 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Counsyl | RCV000411665 | SCV000487365 | uncertain significance | Familial adenomatous polyposis 2 | 2016-06-15 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |