ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.713A>G (p.Asn238Ser) (rs1057517765)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414648 SCV000490627 pathogenic not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.713A>G at the cDNA level, p.Asn238Ser (N238S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant, also published as Asn210Ser and Asn235Ser using alternate transcripts, has been observed at least once in the compound heterozygous state with a MUTYH founder pathogenic variant in an individual with early-onset colorectal cancer and multiple polyps (Dallosso 2008, Jones 2009). Shinmura et al. (2016) found this variant to cause severely defective DNA glycosylase activity and inability to suppress mutations induced by 8-hydroxyguanine. MUTYH Asn238Ser was not observed in large population cohorts (Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. MUTYH Asn238Ser occurs at a position that is conserved across species and is located in the FeS cluster region (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, we consider this variant to be pathogenic.
Ambry Genetics RCV001026079 SCV001188390 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-08 criteria provided, single submitter clinical testing The p.N238S variant (also known as c.713A>G), located in coding exon 9 of the MUTYH gene, results from an A to G substitution at nucleotide position 713. The asparagine at codon 238 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in a compound heterozygous state in individuals with adenomatous polyposis (Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10; Dallosso AR et al. Gut 2008 Sep;57(9):1252-5; Nielsen M et al. Gastroenterology 2009 Feb;136(2):471-6). In addition, a functional assay demonstrated severely reduced (~2%) DNA glycosylase activity in a DNA cleavage activity assay using an A:8OHG substrate (Shinmura K et al. Hum. Mutat. 2016 Apr;37(4):350-3). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV001026079 SCV001348244 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-01 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 238 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes severe defect in the DNA glycosylase activity of MUTYH protein and ability to suppress mutations caused by 8-hydroxyguanine (PMID: 26694661). This variant has been reported in two individuals affected with polyposis and colorectal cancer in compound heterozygous state with a known pathogenic variant (PMID: 18515411, 19732775). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000502397 SCV001361395 likely pathogenic MYH-associated polyposis 2019-10-28 criteria provided, single submitter clinical testing Variant summary: MUTYH c.713A>G (p.Asn238Ser) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. This variant is also reported in the literature as c.671A>G (p.Asn224Ser) and c.704A>G (p.Asn235Ser) using alternate transcripts. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250588 control chromosomes (gnomAD). c.713A>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Dallosso_2008, Jones_2009, Out_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal DNA glycosylase activity (Shinmura_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000502397 SCV001378763 uncertain significance MYH-associated polyposis 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 238 of the MUTYH protein (p.Asn238Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another MUTYH variant in an individual affected with colorectal cancer and multiple colorectal adenomas (PMID: 18515411). This variant is also known as c.704A>G (N235S) in the literature. ClinVar contains an entry for this variant (Variation ID: 372416). This variant has been reported to affect MUTYH protein function (PMID: 26694661). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353995 SCV000592692 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Asn238Ser variant has been reported in the literature in 1/552 proband chromosomes in an individual with MAP and biallelic MUTYH mutations, although no control chromosomes were tested to establish its frequency in the general population (Vogt 2009). The patient from this study also harbored the MUTYH p.Gly396Asp variant, which has been previously reported as pathogenic (Kundu 2009). The p.Asn238 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Asn238Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. MUTYH-associated polyposis (MAP) is inherited in an autosomal recessive manner and two pathogenic variants, one on each chromosome are expected to cause the disorder. The presence of this variant in combination with a reported pathogenic variant increases the likelihood that the p.Asn238Ser variant is pathogenic. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic.

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