ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1435G>T (p.Val479Phe) (rs587782228)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204688 SCV000260144 likely pathogenic MYH-associated polyposis 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 493 of the MUTYH protein (p.Val493Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs587782228, ExAC <0.01%). This variant has been reported as homozygous or biallelic with other pathogenic MUTYH variants in patients with atypical familial adenomatous polyposis and multiple colorectal adenomas (PMID: 16557584, 17949294, 19806110). Furthermore, this variant has also been reported in multiple individuals in the Universal Mutation Database (UMD) as co-occurring with other pathogenic MUTYH variants (PMID: 23729658). In addition, it has been reported as heterozygous in individuals affected with polyposis or colorectal cancer (PMID: 17931073, 20618354). This variant is also known as c.1435G>T (p.Val479Phe) in the literature. ClinVar contains an entry for this variant (Variation ID: 219953). Experimental studies have shown that this missense change results in a partially defective MUTYH protein in an E.coli complementation assay (PMID: 25820570), and is reported to show exon 15 skipping in an ex vivo splicing assay although the data was not shown (PMID: 25368107, 23729658). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000215469 SCV000274772 pathogenic Hereditary cancer-predisposing syndrome 2020-03-20 criteria provided, single submitter clinical testing The c.1477G>T pathogenic mutation (also known as p.V493F) is located in coding exon 15 of the MUTYH gene. The valine at codon 493 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 15 and this nucleotide position is highly conserved in available vertebrate species. This alteration has been identified both in conjunction with a pathogenic MUTYH mutation and in the homozygous state in polyposis patients (Aretz S et al. Int. J. Cancer. 2006 Aug 15;119:807-14; Olschwang S et al. Genet. Test. 2007;11:315-20; Ambry internal data). In addition, this alteration was classified by a functional complementation assay as partially defective (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.V479F (c.1435G>T) in published literature. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice acceptor site, but is not predicted to have a deleterious effect on this splice acceptor site by BDGP. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.
Counsyl RCV000204688 SCV000487353 pathogenic MYH-associated polyposis 2016-05-04 criteria provided, single submitter clinical testing
GeneDx RCV000479402 SCV000565264 likely pathogenic not provided 2017-06-08 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1477G>T at the cDNA level, p.Val493Phe (V493F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant, also known as MUTYH c.1435G>T and Val479Phe using an alternate transcript, has been reported in the homozygous or compound heterozygous state, in at least 3 individuals with multiple colorectal adenomas, with or without colorectal cancer (Aretz 2006, Buecher 2008, Reggoug 2009). This variant was found to be partially defective in an E. coli-based complementation assay (Komine 2015). MUTYH Val493Phe was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Val493Phe occurs at a position that is conserved through mammals and is located in the NUDIX hydrolase domain (Ruggieri 2013, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider MUTYH Val493Phe to be a likely pathogenic variant.
Color Health, Inc RCV000215469 SCV000690532 likely pathogenic Hereditary cancer-predisposing syndrome 2020-11-03 criteria provided, single submitter clinical testing This missense variant replaces valine with phenylalanine at codon 493 in the nudix hydrolase domain of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown the mutant protein to be partially defective in a complementation assay in a MutY-deficient E.coli strain (PMID: 25820570). This variant has been reported in homozygous or compound heterozygous state with other pathogenic variant in individuals affected with multiple colorectal adenomas (PMID: 16557584, 17949294). It has also been reported in a heterozygous individual affected with colorectal cancer (PMID: 17931073). This variant has been identified in 4/271092 chromosomes 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 RCV000204688 SCV000697680 likely pathogenic MYH-associated polyposis 2015-10-16 criteria provided, single submitter clinical testing Variant summary: c.1477G>T affects a conserved nucleotide located at the first position of exon 15, resulting in amino acid change from Val to Phe. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not significantly affect normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. Grandval_2015 predicted that this variant leads to major loss of exon 5 and an inframe deletion (p.Val479_Met492del) based on RT-PCR product sequencing (data not shown). This variant has been reported in homozygous and compound heterozygous state in patients with atypical polyposis, colorectal adenomas, MUTYH associated polyposis. Heterozygous variant was found in 3/87104 control chromosomes at a frequency of 0.0000344 and one patient with sporadic colorectal cancer. One functional study in E.coli showed that protein with this variant partially lost the normal function in suppressing spontaneous mutations (Komine_2015). However, its function in human cells is still not clear. Taken together, this variant was classified as likely pathogenic.

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