Submissions for variant NM_001048174.2(MUTYH):c.954G>A (p.Ser318=)

gnomAD frequency: 0.00004  dbSNP: rs372673338

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165812	SCV000216559	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The c.1038G>A variant (also known as p.S346S), located in coding exon 12 of the MUTYH gene, results from a G to A substitution at nucleotide position 1038. This nucleotide substitution does not change the serine amino acid at codon 346. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant has been reported in the compound heterozygous state with different pathogenic MUTYH mutations in individuals with multiple adenomatous polyps (Olschwang S et al. Genet Test, 2007;11:315-20; Kairupan CF et al. Int. J. Cancer, 2005 Aug;116:73-7; Thibodeau ML et al. Cold Spring Harb Mol Case Stud, 2019 04;5; Ambry internal data). This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). Of note, this alteration is also designated as c.996G>A (p.S332S) in the literature. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000584863	SCV000321910	likely pathogenic	not provided	2023-04-24	criteria provided, single submitter	clinical testing	Splice variant demonstrated to result in the creation of novel splice acceptor site which may result in the deletion of 14 amino acids of exon 12 (Thibodeau et al., 2019); In silico analysis supports a deleterious effect on splicing.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15761860, 17949294, 26269718, 25525159, 21520333, 34758253, 30833417, 25186627)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000255834	SCV000539817	uncertain significance	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent, 1 paper in HGMD
Invitae	RCV000459930	SCV000545703	likely pathogenic	Familial adenomatous polyposis 2	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change affects codon 346 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 14 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs372673338, gnomAD 0.01%). This variant has been observed in individual(s) with breast and pancreatic cancers and/or colonic adenomas (PMID: 15761860, 17949294, 21520333, 25186627, 30833417; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.996G>A and p.S332S. ClinVar contains an entry for this variant (Variation ID: 186251). Studies have shown that this variant results in the activation of a cryptic splice site in exon 12 (PMID: 21520333, 30833417; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000165812	SCV000685535	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This variant is a synonymous variant located in exon 12 of the MUTYH gene. This variant is also known as c.996G>A (p.Ser332=) in the literature based on a different NM_001048171 transcript. Splice site prediction tools suggest that this variant may impact RNA splicing by the creation of a de novo splice acceptor site. Variant g.T is a reference nucleotide in most mammalian species including 4 primate species (https://genome.ucsc.edu/), suggesting that the variant is likely to be tolerated for MUTYH gene function. A RNA study has shown that this variant causes an in-frame deletion of the first 42 bps of exon 12 (r.998_1039del, p.Ala333_Ser346del; https://databases.lovd.nl/shared/variants/0000418407#00023838). The impacted region does not contain a known functional domain and does not show a high evolutionary conservation. To our knowledge, protein functional studies have not been reported for this variant. This variant has been identified in four individuals affected with adenomatous polyposis together with a known pathogenic mutation in the same gene (PMID: 15761860, 17949294, 30833417). Three of these probands were reported to be compound heterozygotes (PMID: 17949294, 30833417). This variant has also been identified in 11/242534 chromosomes (11/108924 Non-Finnish European chromosomes) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000584863	SCV000692628	likely pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	MUTYH: PM3:Strong, PM2:Supporting, PP3
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000584863	SCV000889517	uncertain significance	not provided	2022-11-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0001 (11/108924 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in compound heterozygous individuals with colorectal adenomas and colorectal cancer (PMIDs: 17949294 (2007), 15761860 (2005)), pancreatic cancer (PMID: 30833417 (2019)), and in a heterozygous individual with breast cancer (PMID: 25186627 (2015)). The variant was shown to cause aberrant splicing in tumor RNA (PMID: 30833417 (2019)), however additional studies are needed to corroborate this finding in a germline context. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on MUTYH mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000584863	SCV001480054	likely pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000255834	SCV004024945	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000459930	SCV004198797	uncertain significance	Familial adenomatous polyposis 2	2024-02-07	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000459930	SCV001760034	pathogenic	Familial adenomatous polyposis 2		no assertion criteria provided	clinical testing