Submissions for variant NM_001048174.2(MUTYH):c.1226G>A (p.Arg409Gln)

gnomAD frequency: 0.00002  dbSNP: rs587782120

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130651	SCV000185536	likely benign	Hereditary cancer-predisposing syndrome	2018-04-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000234150	SCV000285925	uncertain significance	Familial adenomatous polyposis 2	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 437 of the MUTYH protein (p.Arg437Gln). This variant is present in population databases (rs587782120, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (CRC) (PMID: 15943555, 35264596). This variant is also known as c.1268G>A. ClinVar contains an entry for this variant (Variation ID: 141933). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect 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.
Counsyl	RCV000234150	SCV000487377	uncertain significance	Familial adenomatous polyposis 2	2016-08-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000587516	SCV000570116	uncertain significance	not provided	2018-05-10	criteria provided, single submitter	clinical testing	This variant is denoted MUTYH c.1310G>A at the cDNA level, p.Arg437Gln (R437Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also published as MUTYH Arg423Gln (R423Q) using alternate nomenclature, has been observed in at least three individuals with sporadic colorectal cancer (Zhou 2005). An E. coli-based complementation assay found that MUTYH Arg437Gln exhibited a spontaneous mutation rate similar to wild-type controls, suggesting that this variant retains protein function (Komine 2015). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MUTYH Arg437Gln is located in the NUDIX domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Arg437Gln 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.?
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290443	SCV000697676	uncertain significance	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1310G>A (p.Arg437Gln) 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 7.9e-06 in 254566 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1310G>A has been reported in the literature in individuals affected with sporadic colorectal cancer (example, Zhou_2005). This report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function (example, Komine_2015). These results showed no damaging effect of this variant in an assay evaluating functional complementation in a MutY-disrupted E Coli strain. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000234150	SCV000837746	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130651	SCV000911085	likely benign	Hereditary cancer-predisposing syndrome	2017-05-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000234150	SCV001253575	uncertain significance	Familial adenomatous polyposis 2	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000130651	SCV002532226	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	curation