ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.986A>G (p.Asn329Ser) (rs754178539)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235990 SCV000293288 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1070A>G at the cDNA level, p.Asn357Ser (N357S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. MUTYH Asn357Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Asn357Ser 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 MUTYH pathogenic variants on opposite chromosomes.
Ambry Genetics RCV000562865 SCV000670170 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-30 criteria provided, single submitter clinical testing The p.N357S variant (also known as c.1070A>G), located in coding exon 12 of the MUTYH gene, results from an A to G substitution at nucleotide position 1070. The asparagine at codon 357 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000562865 SCV000685536 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-29 criteria provided, single submitter clinical testing
Mendelics RCV000708793 SCV000837756 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV000708793 SCV001386611 uncertain significance MYH-associated polyposis 2020-07-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 357 of the MUTYH protein (p.Asn357Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs754178539, ExAC 0.01%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 246011). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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