Submissions for variant NM_001048174.2(MUTYH):c.523C>T (p.Arg175Cys)

gnomAD frequency: 0.00004  dbSNP: rs587780748

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123152	SCV000166456	uncertain significance	Familial adenomatous polyposis 2	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the MUTYH protein (p.Arg203Cys). This variant is present in population databases (rs587780748, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer or multiple colorectal adenomas (PMID: 17949294, 27978560, 28135145). This variant is also known as c.565C>T (p.Arg189Cys). ClinVar contains an entry for this variant (Variation ID: 135988). 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.
Ambry Genetics	RCV000220980	SCV000273013	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	The p.R203C variant (also known as c.607C>T), located in coding exon 8 of the MUTYH gene, results from a C to T substitution at nucleotide position 607. The arginine at codon 203 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was previously reported in an individual with greater than 5 colorectal adenomas; however, no other alterations in the MUTYH gene were detected and this alteration was classified as a variant of unknown significance (Olschwang S et al. Genet. Test. 2007;11:315-20). This alteration has also been reported in 1/450 patients with colorectal cancer diagnosed under the age of 50 years who were tested with a multi-gene panel (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet., 2018 04;14:e1007352). 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.
Counsyl	RCV000123152	SCV000487326	uncertain significance	Familial adenomatous polyposis 2	2015-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000478528	SCV000565255	uncertain significance	not provided	2022-04-16	criteria provided, single submitter	clinical testing	Observed in individuals with a personal history of adenomatous polyps or colorectal cancer (Olschwang 2007, Yurgelun 2017, Pearlman 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.565C>T (p.Arg189Cys); This variant is associated with the following publications: (PMID: 17949294, 26944241, 28135145, 27978560, 28502729, 29596542, 33553733)
Color Diagnostics, LLC DBA Color Health	RCV000220980	SCV000685649	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 203 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 individuals affected with polyposis or colorectal cancer (PMID: 17949294, 28135145, 27978560), melanoma, kidney cancer, uterine cancer, or breast cancer (PMID: 29684080). This variant has been identified in 12/282786 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478528	SCV001134481	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with suspected Lynch syndrome and/or polyposis (PMID: 28502729 (2017)), colorectal cancer and colonic adenomas (PMIDs: 27978560 (2017), 28135145 (2017), 17949294 (2007)), and kidney renal papillary cell carcinoma (PMID: 29684080 (2018)). In a breast cancer association study, this variant was not seen in individuals with cancer but was seen in healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00014 (5/35430 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 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.
Mendelics	RCV000123152	SCV001135263	uncertain significance	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824618	SCV002074369	uncertain significance	not specified	2022-01-20	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.607C>T (p.Arg203Cys) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) 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 4.4e-05 in 251456 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0046), allowing no conclusion about variant significance. The variant c.607C>T (aka. c.565C>T (p.Arg189Cys)) has been reported in the literature in individuals affected with colorectal cancer and polyps (Olschwang_2007, Rey_2017, Pearlman_2016, Yurgelun_2017). However, these reports 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. Seven 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.
Baylor Genetics	RCV000123152	SCV004198811	uncertain significance	Familial adenomatous polyposis 2	2024-03-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123152	SCV004841703	uncertain significance	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 203 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 individuals affected with polyposis or colorectal cancer (PMID: 17949294, 28135145, 27978560), melanoma, kidney cancer, uterine cancer, or breast cancer (PMID: 29684080). This variant has been identified in 12/282786 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.