Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000204688 | SCV000260144 | pathogenic | Familial adenomatous polyposis 2 | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 493 of the MUTYH protein (p.Val493Phe). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587782228, gnomAD 0.002%). This missense change has been observed in individuals with polyposis or colorectal cancer and/or small cell lung cancer (PMID: 16557584, 17931073, 17949294, 19806110, 20618354, 23729658, 33504652). This variant is also known as c.1435G>T (p.Val479Phe). ClinVar contains an entry for this variant (Variation ID: 219953). 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: 25820570). Studies have shown that this missense change results in skipping of exon 15 skipping, but is expected to preserve the integrity of the reading-frame (Invitae). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000215469 | SCV000274772 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-15 | 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. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. 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 | Familial adenomatous polyposis 2 | 2016-05-04 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000479402 | SCV000565264 | likely pathogenic | not provided | 2021-05-06 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); 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); Published functional studies demonstrate a damaging effect: partially defective base excision repair activity in a yeast-based complementation assay (Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1435G>T, p.Val479Phe; This variant is associated with the following publications: (PMID: 18787472, 29684080, 22493355, 22538434, 27631816, 21279954, 25368107, 26689913, 25820570, 20618354, 19806110, 16557584, 17931073, 17949294) |
| Color Diagnostics, |
RCV000215469 | SCV000690532 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-18 | 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 the homozygous or compound heterozygous state 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, |
RCV000204688 | SCV000697680 | likely pathogenic | Familial adenomatous polyposis 2 | 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. |
| Fulgent Genetics, |
RCV002503805 | SCV002807691 | likely pathogenic | Familial adenomatous polyposis 2; Gastric cancer | 2021-07-21 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000204688 | SCV003828432 | likely pathogenic | Familial adenomatous polyposis 2 | 2022-01-06 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004530223 | SCV004113352 | pathogenic | MUTYH-related disorder | 2023-07-17 | criteria provided, single submitter | clinical testing | The MUTYH c.1477G>T variant is predicted to result in the amino acid substitution p.Val493Phe. This variant was reported in multiple individuals with MUTYH-associated polyposis, colorectal cancer, or small cell lung cancer (see for example Aretz et al 2006. PubMed ID: 16557584; Küry et al 2007. PubMed ID: 17931073; Olschwang et al 2007. PubMed ID: 17949294; Reggoug et al 2009. PubMed ID: 19806110; Morak et al 2010. PubMed ID: 20618354; Tlemsani et al 2021. PubMed ID: 33504652). A published functional study demonstrated the damaging effect of this variant (Komine K et al 2015. PubMed ID: 25820570). This variant is also known as c.1435G>T (p.Val479Phe). This variant is reported in 0.0033% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45796229-C-A). This variant is interpreted as pathogenic. |
| Baylor Genetics | RCV000204688 | SCV004198888 | likely pathogenic | Familial adenomatous polyposis 2 | 2023-08-21 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000204688 | SCV004833296 | likely pathogenic | Familial adenomatous polyposis 2 | 2023-10-02 | 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. |
| Laboratory for Molecular Medicine, |
RCV000204688 | SCV004848140 | likely pathogenic | Familial adenomatous polyposis 2 | 2018-08-22 | criteria provided, single submitter | clinical testing | The p.Val493Phe variant (also known as p.Val479Phe in the literature) in MUTYH has been reported in 1 compound heterozygous individual with MUTYH-associated attenuated familial adenomatous polyposis (FAP; Aretz 2006), 1 compound heterozygous individual with colorectal adenomas (Reggoug 2009), 1 homozygous individual with sporadic colorectal cancer (CRC; Kury 2007), and 1 heterozygous individual with CRC with no second allele specified (Kury 2007). This variant has also been reported in ClinVar (Variation ID 219953). This variant has been identified in 3/15010 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587782228). This frequency is low enough to be consistent with the frequency of MUTYH-related attenuated FAP in the general population. In vitro functional studies provide some evidence that the p.Val493Phe variant may impact protein function (Grandval 2015, Komine 2015). Computational prediction tools and conservation analysis suggest that the p.Val493Phe variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Val493Phe variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP3 |