Submissions for variant NM_001048174.2(MUTYH):c.629A>G (p.Asn210Ser)

dbSNP: rs1057517765

Total submissions: 7

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	2023-02-08	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 polyps as well as colorectal cancer and in an individual 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; Ambry internal data). It was also reported in a patient with features of MUTYH associated polyposis, but no co-occurring MUTYH variant was reported (Nielsen M et al. Gastroenterology, 2009 Feb;136:471-6). 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). Based on an internal structural analysis, this variant is more destabilizing to the MUTYH active site than other nearby pathogenic variants (Ambry internal data; Luncsford PJ et al. J Mol Biol, 2010 Oct;403:351-70; Woods RD et al. Nucleic Acids Res, 2016 Jan;44:801-10; Russelburg LP et al. ACS Chem Biol, 2020 01;15:93-102). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001026079	SCV001348244	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	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) and in one individual with pancreatic cancer (PMID: 34659905). 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	Familial adenomatous polyposis 2	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000502397	SCV001378763	uncertain significance	Familial adenomatous polyposis 2	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 238 of the MUTYH protein (p.Asn238Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer and/or multiple colorectal adenomas (PMID: 18515411). This variant is also known as c.704A>G (N235S). ClinVar contains an entry for this variant (Variation ID: 372416). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 26694661). 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.
Baylor Genetics	RCV000502397	SCV004199435	pathogenic	Familial adenomatous polyposis 2	2021-12-31	criteria provided, single submitter	clinical testing
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.