ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.954G>A (p.Ser318=) (rs372673338)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165812 SCV000216559 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-13 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 amino acid at codon 346. This alteration has been reported in the compound heterozygous state with different pathogenic MUTYH mutations in individuals with multiple adenomatous polyps (<span style="background-color: initial;">Olschwang S et al. Genet. Test. 2007;11(3):315-20; Kairupan CF et al. Int. J. Cancer. 2005 Aug;116(1):73-7; Thibodeau ML et al. Cold Spring Harb Mol Case Stud. 2019 04;5<span style="background-color: initial;">). This alteration was also detected on a 25-gene panel test in a woman of Western/Northern European ancestry who was diagnosed with breast cancer before age 50 (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. <span style="background-color: initial;">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<span style="background-color: initial;">; however, direct evidence is insufficient at this time (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000584863 SCV000321910 likely pathogenic not provided 2020-03-26 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 2019); This variant is associated with the following publications: (PMID: 15761860, 17949294, 26269718, 25525159, 21520333, 30833417)
Laboratory for Molecular Medicine, Partners HealthCare 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 uncertain significance MYH-associated polyposis 2020-10-15 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. This variant is present in population databases (rs372673338, ExAC 0.01%). This variant has been observed in individual(s) with colonic adenomas (PMID: 17949294, 21520333, 15761860) and has also been seen in individual(s) with pancreatic and breast cancers (PMID: 30833417, 25186627). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.996G>A and p.S332S in the literature. ClinVar contains an entry for this variant (Variation ID: 186251). Experimental studies have reported that this silent change promotes aberrant splicing, leading to the production of an alternative MUTYH transcript with an in-frame deletion of first 42 bp of exon 12 (PMID: 21520333, 30833417). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000165812 SCV000685535 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-12 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 (, 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; 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 Praxis fuer Humangenetik Tuebingen RCV000584863 SCV000692628 likely pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000584863 SCV000889517 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing
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
Genomics England Pilot Project,Genomics England RCV000459930 SCV001760034 pathogenic MYH-associated polyposis no assertion criteria provided clinical testing

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