ClinVar Genomic variation as it relates to human health

The MUTYH c.1396G>T (p.Glu466Ter) variant, also referred to as p.Glu480Ter, is a stop-gained variant that is predicted to result in premature truncation of the protein. The p.Glu466Ter variant has been reported in at least four studies in which it is found in a homozygous state in 16 individuals with polyposis. Six individuals also developed colorectal cancer with an age of onset ranging between 35 to 65 years (Jones et al. 2002; Vogt et al. 2009; Inra et al. 2015; Khan et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.038835 in the Gujarati Indian in Houston, TX population of the 1000 Genomes Project. Functional data from Ali et al. (2008) showed that the p.Glu466Ter variant protein had dysfunctional glycosylase and DNA binding activity compared with wild type protein. Based on the evidence and potential impact of stop-gained variants, the p.Glu466Ter variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change creates a premature translational stop signal (p.Glu480*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs121908381, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis syndrome (MAP) (PMID: 12393807, 12853198, 15635083, 17369389, 17874208, 19032956, 19732775). It is commonly reported in individuals of South Asian ancestry (PMID: 12853198). This variant is also known as c.1396G>T (p.Glu466X or E466X). ClinVar contains an entry for this variant (Variation ID: 5297). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

This variant changes 1 nucleotide in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is also known as E466X (c.1396G>T) based on an alternate transcript NM_001048171. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that the truncated mutant protein is expressed at low levels in E. coli and exhibits lack of glycosylase activity and DNA-binding activity (PMID: 18534194). This variant has been reported in over ten homozygous individuals affected with polyposis and/or colorectal cancer (PMID: 12393807, 12853198, 17874208, 19732775, 28533537). This variant has been identified in 13/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The p.Glu480X variant in MUTYH (also referred to as p.Glu466X in the literature) has been reported in at least 9 homozygotes with MUTYH-associated polyposis and segregated in 2 affected homozygotes from one family (Vogt 2009 PMID: 19732775, Inra 2015 PMID: 25590978). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 5297). This variant has been identified in 0.2% (10/4836) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 480, which is predicted to lead to a truncated or absent protein. In vitro functional studies provide support that the p.Glu480X variant impacts protein activity (Ali 2008 PMID: 18534194). Biallelic loss of function of the MUTYH gene is an established disease mechanism in MUTYH-associated polyposis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MUTYH-associated polyposis. ACMG/AMP Criteria applied: PVS1, PM3, PP1_Moderate, PM2_Supporting, PS3_Supporting.

A homozygous nonsense variation in exon 14 of the MUTYH gene that results in a stop codon and premature truncation of protein at codon 477 was detected. The observed variation has previously been reported in patients and families affected with colorectal cancer (Jones et al. 2002, Sampson et al. 2003) and it lies in the NUDIX domain of the MUTYH_HUMAN protein. An experimental study suggests that the variant results in defective glycosylase and DNA-binding activity. The observed variant c.1429G>T (p.Glu477Ter) has a minor allele frequency of 0.1% and 0.01% in the 1000 genomes and ExAC databases respectively. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the Glu477Ter variant meets our criteria to be classified as pathogenic.

Variant summary: MUTYH c.1438G>T (p.Glu480X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.2e-05 in 251492 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is lower than the maximum expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.00042 vs 0.0046). The variant (also referred to as p.Glu466X) has been reported in the literature in several homozygous individuals affected with MUTYH-associated Polyposis (e.g. Jones_2009, Vogt_2009), and many of the reported cases were noted to be of Indian ancestry (e.g. Sampson_2003, Dolwani_2007, Inra_2015, Khan_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the truncated protein product had lost its glycosylase- and DNA binding activity (Ali_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: defective glycosylase and DNA binding activities (Ali 2008); This variant is associated with the following publications: (PMID: 25590978, 19032956, 26202870, 27194394, 26902849, 23035301, 18534194, 33130102, 32411090, 19732775, 12393807, 12853198, 17369389, 15635083, 17874208, 28533537, 28790112, 28381238, 27631816, 30609409, 30604180)

This variant is also referred to as p .Glu466Ter in the literature. This nonsense variant found in exon 14 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as compound heterozygous and homozygous change in patients with MUTYH-related disorders (PMID: 12393807, 12853198, 15635083, 17369389, 17874208, 19032956, 19732775). This variant is commonly reported in individuals of South Asian ancestry (PMID: 12853198, 28533537, 17369389). Loss-of-function variation in MUTYH is an established mechanism of disease (PMID: 18534194, 20663686). Functional studies showed that the c.1429G>T (p.Glu477Ter) variant alters the function of the MUTYH protein (PMID: 18534194). The c.1429G>T (p.Glu477Ter) variant is present in the gnomAD population database at a frequency of 0.005% (13/ 251492) in the heterozygous state and a frequency of 0.0003% (1 /251492) in the homozygous state. Based on the available evidence, the c.1429G>T (p.Glu477Ter) variant is classified as Pathogenic.

This variant changes 1 nucleotide in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is also known as E466X (c.1396G>T) based on an alternate transcript NM_001048171. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that the truncated mutant protein is expressed at low levels in E. coli and exhibits lack of glycosylase activity and DNA-binding activity (PMID: 18534194). This variant has been reported in over ten homozygous individuals affected with polyposis and/or colorectal cancer (PMID: 12393807, 12853198, 17874208, 19732775, 28533537). This variant has been identified in 13/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The p.E480* pathogenic mutation (also known as c.1438G>T), located in coding exon 14 of the MUTYH gene, results from a G to T substitution at nucleotide position 1438. This changes the amino acid from a glutamic acid to a stop codon within coding exon 14. This mutation was first reported in the literature in the homozygous state in three unrelated individuals with greater than 100 colorectal adenomas (Jones S et al. Hum. Mol. Genet. 2002 Nov;11:2961-7). It has since been observed in multiple individuals with a personal history of polyposis in both a compound heterozygous and homozygous state (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Inra JA et al. Genet. Med. 2015 Oct;17:815-21; Khan N et al. Sci Rep. 2017 May;7:2214), as well as a pediatric patient with a high-grade midline glioma (Kline CN et al. Neuro-oncology. 2016 05;18:752-3). Current data indicates that this alteration is more frequently identified in individuals of Asian Indian descent and has been described as a possible founder mutation in individuals of Indian ancestry (Eliason K et al. J. Med. Genet. 2005 Jan;42:95-6; Dolwani S et al. Gut. 2007 Apr;56:593; Sampson J et al. Lancet. 2003 Jul 5;362:39-41; Khan N et al. Sci Rep. 2017 May;7:2214). Furthermore, an in vitro functional study demonstrated that the E480* mutant protein was completely devoid of both glycosylase and DNA-binding activities, both of which are essential for the base excision repair properties of the wild-type MUTYH protein (Ali M et al. Gastroenterology. 2008 Aug;135:499-507). This mutation is also designated as E466X and 1396G>T in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

The observed missense variant c.534G>T (p.Lys178Asn) in MSH3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Lys178Asn has allele frequency 0.007% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT - Tolerated and Mutation Taster - Polymorphism) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid on MSH3 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Lys at position 178 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).

The MUTYH p.Glu480* variant has been previously reported in numerous publications in individuals with multiple colorectal adenomas and MUTYH-associated polyposis (MAP; selected publications: Jones 2002, Vogt 2009). This variant leads to a premature stop codon at position 480, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MUTYH gene are an established disease mechanism in MAP. In addition, a functional study demonstrated that this variant led to absent glycosylase and no DNA binding activity (Ali 2008). In summary, based on the above information, this variant is classified as pathogenic.

Founder variant in the British Indian population