ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1333G>A (p.Ala445Thr) (rs192816572)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130207 SCV000185045 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing <span style="background-color:initial">The p.A473T variant (also known as c.1417G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1417. The alanine at codon 473 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in several patient cohorts including an early-onset colorectal cancer patient, an individual with greater than 5 colorectal adenomas, and an individual who underwent clinical genetic testing for Lynch syndrome; however, no other alterations in the MUTYH gene were detected in these cases, and p.A473T was classified as a variant of unknown significance (Fleischmann C et al. Int. J. Cancer. 2004 Apr;109:554-8; Olschwang S et al. Genet. Test. 2007;11:315-20; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20<span style="background-color:initial">). Functional studies of this variant demonstrate that it has near-wild type function in an E. coli-based complementation assay; however, glycosylase assays have never been conducted on this variant (Komine K et al. Hum. Mutat. 2015 Jul;36:704-11<span style="background-color:initial">). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Of note, this alteration is also designated as p.A459T in published literature. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000656912 SCV000211418 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1417G>A at the cDNA level, p.Ala473Thr (A473T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant, also known as c.1375G>A, p.Ala459Thr (A459T) and c.1408G>A, p.Ala470Thr (A470T), using alternate nomenclature, has been observed in the heterozygous state in at least three individuals with a personal history of colon or another Lynch syndrome-related cancer and/or polyps as well as in one individual with sarcoma and another with breast cancer (Fleischmann 2004, Olschwang 2007, Tung 2015, Yurgelun 2015, Ballinger 2016). Komine et al. (2015) reported that MUTYH Ala473Thr retained base excision repair activity after finding a spontaneous mutation rate comparable to wild-type on a yeast-based complementation assay. MUTYH Ala473Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). MUTYH Ala473Thr is located within the Nudix hydrolase domain (UniProt, Ruggieri 2013). While protein-based in-silico analysis supports that this variant does not alter protein structure/function, splicing models predict that this variant may increase a cryptic splice donor site upstream of the natural splice donor site of intron 14 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MUTYH Ala473Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.?
Invitae RCV000198237 SCV000254702 uncertain significance MYH-associated polyposis 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 473 of the MUTYH protein (p.Ala473Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs192816572, ExAC 0.003%). This variant has been observed in individual(s) with clinical features of MUTYH-associated polyposis (PMID: 17949294, 14991577, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1375G>A (p.A459T) in the literature. ClinVar contains an entry for this variant (Variation ID: 141614). This variant has been reported not to substantially affect MUTYH protein function (PMID: 25820570). This variant disrupts the p.Ala473 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16134146, 25820570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Health, Inc RCV000130207 SCV000685573 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-29 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 473 of the MUTYH protein. This variant is also known as c.1375G>A (p.Ala459Met) based on an alternative transcript (NM_001048171). 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). Splice site prediction tools suggest that this variant may strengthen an alternative splice donor site. An RNA study using lymphoblastoid cell lines derived from a phenotypically normal subject has shown that this variant leads to the use of the alternative splice donor site (PMID: 31687339), creating a frameshift in the transcript. The clinical relevance of this observation is not known. A functional study has shown that this variant protein leads to similar base excision repair activity in comparison with the wild-type protein in a bacterial complementation assay (PMID: 25820570). This variant has been reported in individuals affected with Lynch syndrome–associated cancer and/or polyps (PMID: 25980754), multiple colorectal adenomas (PMID: 17949294), and breast cancer (PMID: 25186627). This variant has also been identified in 15/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212718 SCV000711961 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala473Thr var iant in MUTYH has been reported in the heterozygous state in one individual with colorectal cancer (Fleischmann 2004) and one individual who was tested for a Ly nch Syndrome-associated cancer or colorectal polyps (Yurgelun 2015). Another stu dy reported this variant in an unspecified number of individuals with adenomatou s polyposis (Olschwang 2007; variant reported as Ala459Thr). In vitro functional studies provide some evidence that the p.Ala473Thr variant may not impact prote in function (Komine 2015). However, these types of assays may not accurately rep resent biological function. This variant has also been reported in ClinVar (Vari ation ID 141614) and in 0.02% (14/129192) of European chromosomes by gnomAD (htt p:// Computational prediction tools and conservation analysis support that the p.Ala473Thr variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary , while the clinical significance of the p.Ala473Thr variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BP 4, BS3_P.
Counsyl RCV000198237 SCV000788479 uncertain significance MYH-associated polyposis 2017-01-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656912 SCV000806342 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656912 SCV000888308 uncertain significance not provided 2019-04-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212718 SCV000917800 uncertain significance not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1417G>A (p.Ala473Thr) results in a non-conservative amino acid change located in the C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 121596 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (1.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.1417G>A has been reported in the literature in individuals affected with colorectal cancer or breast cancer (Fleischmann_2004, Olschwang_2007, Tung_2014, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. One publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Komine_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000198237 SCV001253574 uncertain significance MYH-associated polyposis 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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