ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1038G>A (p.Ser346=) (rs372673338)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165812 SCV000216559 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000584863 SCV000692628 likely pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing
Color RCV000165812 SCV000685535 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
GeneDx RCV000584863 SCV000321910 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1038G>A at the DNA level. Although the variant is silent at the coding level, preserving a Serine at codon 346, it is predicted to cause abnormal splicing by multiple in silico models. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has been reported in at least three individuals with a history of polyposis who are also reported to harbor one of the two common MUTYH pathogenic variants; however, phase is not reported (Kairupan 2005, Olschwang 2007). MUTYH c.1038G>A was observed at an allele frequency of 0.01% (7/56,778) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 1038, is not conserved. Based on currently available evidence, it is unclear whether MUTYH c.1038G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Invitae RCV000459930 SCV000545703 uncertain significance MYH-associated polyposis 2018-10-18 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. This variant is present in population databases (rs372673338, ExAC 0.01%). This variant has been reported with other pathogenic MUTYH variants in individuals affected with multiple colorectal adenomas (PMID: 17949294, 21520333). 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). 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.
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000584863 SCV000889517 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing

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