Submissions for variant NM_001048174.2(MUTYH):c.1102+1G>A

gnomAD frequency: 0.00001  dbSNP: rs587781337

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129098	SCV000183809	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	clinical testing	The c.1186+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the MUTYH gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the missing amino acids is unknown; however, based on an internal structural analysis, coding exon 12 skipping would disrupt the structure of the NUDIX domain (Ambry internal data; Russelburg LP et al. ACS Chem Biol, 2020 01;15:93-102). This variant was identified in conjunction with a pathogenic MUTYH variant in a proband with adenomatous polyposis, but the phase of the two variants was unknown (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000503838	SCV000941079	pathogenic	Familial adenomatous polyposis 2	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 of the MUTYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587781337, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 140874). Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts a region of the MUTYH protein in which other variant(s) (p.Leu388Pro) have been determined to be pathogenic (PMID: 16134147, 16941501, 17949294, 20848659, 23322991, 25820570). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000503838	SCV002017825	likely pathogenic	Familial adenomatous polyposis 2	2019-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001353653	SCV002568748	likely pathogenic	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16879101, 20816984, 23108399, 28152038)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001353653	SCV004024934	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532544	SCV004112563	likely pathogenic	MUTYH-related disorder	2023-01-27	criteria provided, single submitter	clinical testing	The MUTYH c.1186+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant and another change at the same canonical splice site have been reported in the literature as likely pathogenic (LaDuca et al. 2017. PubMed ID: 28152038; c.1186+2T>C, Jian et al. 2017. PubMed ID: 29093764; Hata et al. 2020. PubMed ID: 32029870). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45797332-C-T). Variants that disrupt the consensus splice donor site in MUTYH are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129098	SCV004358557	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the +1 position of intron 12 of the MUTYH gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, RNA studies have not been published for this variant, however it is expected to result in the skipping of exon 12 (ClinVar: SCV000941079.5). Pathogenic missense variants have been identified in exon 12 (ClinVar Variation IDs: 406845, 421574), indicating this exon is important for function. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 1/249520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000503838	SCV004826232	pathogenic	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353653	SCV000592710	uncertain significance	not provided		no assertion criteria provided	clinical testing