Submissions for variant NM_001048174.2(MUTYH):c.1351G>A (p.Glu451Lys)

gnomAD frequency: 0.00006  dbSNP: rs376790729

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165664	SCV000216402	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.E479K variant (also known as c.1435G>A), located in coding exon 14 of the MUTYH gene, results from a G to A substitution at nucleotide position 1435. The glutamic acid at codon 479 is replaced by lysine, an amino acid with similar properties. This alteration was found in an individual with 10 to 100 adenomas at age 41 and also in her daughter, who was affected with 20 to 30 adenomas first diagnosed in her teens. A second MUTYH alteration was not identified in this patient (Morak M et al. Clin. Genet. 2010 Oct;78:353-63). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). Of note, this alteration is also known as c.1393G>A (p.Glu465Lys) in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200800	SCV000254703	uncertain significance	Familial adenomatous polyposis 2	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 479 of the MUTYH protein (p.Glu479Lys). This variant is present in population databases (rs376790729, gnomAD 0.008%). This missense change has been observed in individual(s) with multiple colon adenomas (PMID: 20618354). ClinVar contains an entry for this variant (Variation ID: 186129). 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 tolerated. 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000200800	SCV000257794	uncertain significance	Familial adenomatous polyposis 2	2015-03-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000480347	SCV000567119	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	Observed without a second MUTYH variant two related individuals with multiple adenomas and in an individual with soft tissue sarcoma (Morak et al., 2010; Ballinger et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as Glu476Lys; This variant is associated with the following publications: (PMID: 27498913, 20618354, 23108399)
Color Diagnostics, LLC DBA Color Health	RCV000165664	SCV000910969	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 479 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified as a heterozygous variant in two related individuals affected with polyposis (PMID: 20618354) and an individual affected with colorectal cancer (PMID: 21901162). In a large international case-control meta-analysis, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 11/282904 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.
Sema4, Sema4	RCV000165664	SCV002532238	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	curation
Baylor Genetics	RCV000200800	SCV004198853	uncertain significance	Familial adenomatous polyposis 2	2024-03-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000480347	SCV004227830	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000200800	SCV004825216	uncertain significance	Familial adenomatous polyposis 2	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 479 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified as a heterozygous variant in two related individuals affected with polyposis (PMID: 20618354) and an individual affected with colorectal cancer (PMID: 21901162). In a large international case-control meta-analysis, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 11/282904 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689639	SCV005184628	uncertain significance	not specified	2024-05-24	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1435G>A (p.Glu479Lys) results in a conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1435G>A has been reported in the literature in at least one heterozygous individual affected with an attenuated familial adenomatous polyposis III colorectal neoplasia (e.g. Morak_2010). This report does not provide sufficient evidence to allow unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34130653, 20618354). ClinVar contains an entry for this variant (Variation ID: 186129). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics	RCV000480347	SCV005186673	uncertain significance	not provided		criteria provided, single submitter	not provided
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480347	SCV005622954	uncertain significance	not provided	2024-12-03	criteria provided, single submitter	clinical testing	The MUTYH c.1435G>A (p.Glu479Lys) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)) and attenuated familial adenomatous polyposis (AFAP) (PMID: 20618354 (2010)). This variant has also been identified in reportedly healthy individuals (PMID: 29641532 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000062 (8/129202 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.