Submissions for variant NM_001048174.2(MUTYH):c.1007G>A (p.Arg336His)

gnomAD frequency: 0.00003  dbSNP: rs587780741

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123138	SCV000166440	uncertain significance	Familial adenomatous polyposis 2	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 364 of the MUTYH protein (p.Arg364His). This variant is present in population databases (rs587780741, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 21520333, 28873162, 32390558). ClinVar contains an entry for this variant (Variation ID: 135980). 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. 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.
Ambry Genetics	RCV000131222	SCV000186174	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-15	criteria provided, single submitter	clinical testing	The p.R364H variant (also known as c.1091G>A), located in coding exon 12 of the MUTYH gene, results from a G to A substitution at nucleotide position 1091. The arginine at codon 364 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1040 individuals with advanced cancer undergoing paired tumor-germline sequencing and was classified as a variant of unknown significance by authors (Mandelker D et al. JAMA, 2017 09;318:825-835). This alteration was also identified once in a cohort of gastrointestinal cancer, polyposis, and/or hereditary gastrointestinal system cancer history cases, but no other alterations in MUTYH were reported (Yalcintepe S et al. Tumori, 2020 Dec;106:510-517). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000131222	SCV000685539	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 364 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 performed for this variant. This variant has been reported in an individual affected with unspecified cancer (PMID: 28873162). This variant has been identified in 7/281190 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	RCV000131222	SCV002532201	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004530051	SCV004115547	uncertain significance	MUTYH-related disorder	2022-11-18	criteria provided, single submitter	clinical testing	The MUTYH c.1091G>A variant is predicted to result in the amino acid substitution p.Arg364His. This variant has been reported in an individual with advanced cancer and an individual with a Lynch syndrome indication (eTable, Mandelker et al. 2017. PubMed ID: 28873162; Table 4, Yalcintepe et al. 2020. PubMed ID: 32390558). This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45797428-C-T) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/135980/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000123138	SCV004198833	uncertain significance	Familial adenomatous polyposis 2	2023-10-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477523	SCV004222069	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00029 (7/24540 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a cohort of individuals with advanced cancer undergoing paired tumor-germline sequencing (PMID: 28873162 (2017)), as well as in an individual with gastrointestinal cancer (PMID: 32390558 (2018)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in an unaffected individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479012	SCV004223370	uncertain significance	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1091G>A (p.Arg364His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249798 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1091G>A has been reported in the literature in individuals affected with Lynch syndrome (e.g. Yalcintepe_2020), acute megakaryoblastic leukemia (e.g. Zhang_2015), prostate adenocarcinoma or other cancer (e.g. Barreiro_2022) without evidence for causality and often reported as a VUS. These report(s) do not provide 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: 34816434, 32390558, 26580448). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.