Submissions for variant NM_001048174.2(MUTYH):c.1381G>A (p.Ala461Thr)

gnomAD frequency: 0.00006  dbSNP: rs587782263

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130986	SCV000185906	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing	The p.A489T variant (also known as c.1465G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1465. The alanine at codon 489 is replaced by threonine, an amino acid with similar properties. This variant has been reported in conjunction with two pathogenic mutations in the MUTYH gene in a male with polyposis, jaw exostosis and sebaceous cysts at age 34 (Kairupan CF et al. Int. J. Cancer 2005 Aug;116:73-7), and in an individual with 20 polyps at age 51 and breast cancer diagnosed at age 48 (Jo WS et al. Clin. Gastroenterol. Hepatol. 2005 Oct;3:1022-8). The MUTYH c.933+3A>C and p.A489T variants have co-occurred multiple times with other known MUTYH pathogenic mutations in unrelated individuals who are affected with polyposis, however the phase has not been determined (Kairupan CF et al. Int. J. Cancer. 2005 Aug;116(1):73-7; Ambry internal data). The p.A489T variant has also been reported as a monoallelic variant in an individual with an attenuated familial adenomatous polyposis phenotype (Morak M et al. Clin. Genet. 2010 Oct;78:353-63). An assay measuring base-excisional repair function found this alteration to result in partially defective protein function (Komine K et al. Hum. Mutat. 2015 Jul;36(7):704-11). Of note, this alteration is also designated as p.A475T (c.1423G>A) in published literature. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203814	SCV000261194	uncertain significance	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 489 of the MUTYH protein (p.Ala489Thr). This variant is present in population databases (rs587782263, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal polyposis (PMID: 16234049; Invitae; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as G1423A (A475T). ClinVar contains an entry for this variant (Variation ID: 142138). 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). 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.
GeneDx	RCV000486816	SCV000568578	uncertain significance	not provided	2024-02-02	criteria provided, single submitter	clinical testing	Observed as a single monoallelic variant, as well as with a pathogenic MUTYH variant in individuals with multiple polyps and/or colon cancer; however, it was unknown if the variants were on the same or opposite alleles (in cis or in trans) (PMID: 16234049, 15761860, 20618354, 35668106); Published functional studies demonstrate partially defective base excision repair activity in a yeast-based complementation assay (PMID: 25820570); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1423G>A or p.(A475T); This variant is associated with the following publications: (PMID: 15761860, 20618354, 16234049, 35668106, 23108399, 25820570)
Color Diagnostics, LLC DBA Color Health	RCV000130986	SCV000685584	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 489 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 the mutant protein to be partially defective for base excision repair activity (PMID: 25820570). This variant has been reported in individuals affected with polyposis (PMID: 15761860, 16234049, 20618354, 25820570) or colorectal cancer (PMID: 35668106). However, it often co-occurs with another pathogenic variant MUTYH c.933+3A>C, suggesting it may be a linked polymorphism (Color internal data). This variant has been identified in 11/282784 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.
Counsyl	RCV000203814	SCV000797927	uncertain significance	Familial adenomatous polyposis 2	2018-02-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000486816	SCV000806345	uncertain significance	not provided	2018-01-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781620	SCV000919797	uncertain significance	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1465G>A (p.Ala489Thr) results in a non-conservative amino acid change located in the MutY, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251694 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1465G>A has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Kairupan_2005, Jo_2005, Morak_2010). These data indicate that the variant may be associated with disease. One internally tested patient carry the variant of interest and two pathogenic MUTYH variants (c.933+3A>C, c.1187G>A/p.G396D), providing supporting evidence for a benign role for this variant. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 32% of normal base excision repair (BER) glycosylase activity (Komine_2015). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000486816	SCV001713010	uncertain significance	not provided	2020-06-05	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000486816	SCV002502525	uncertain significance	not provided	2020-04-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000203814	SCV004198844	uncertain significance	Familial adenomatous polyposis 2	2024-02-25	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130986	SCV004228049	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000203814	SCV004833519	uncertain significance	Familial adenomatous polyposis 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 489 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 the mutant protein to be partially defective for base excision repair activity (PMID: 25820570). This variant has been reported in individuals affected with polyposis (PMID: 15761860, 16234049, 20618354, 25820570) or colorectal cancer (PMID: 35668106). However, it often co-occurs with another pathogenic variant MUTYH c.933+3A>C, suggesting it may be a linked polymorphism (Color internal data). This variant has been identified in 11/282784 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.