Submissions for variant NM_001048174.2(MUTYH):c.836G>A (p.Arg279Gln)

gnomAD frequency: 0.00009  dbSNP: rs140156029

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129507	SCV000184280	likely benign	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467096	SCV000545750	uncertain significance	Familial adenomatous polyposis 2	2024-02-01	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 307 of the MUTYH protein (p.Arg307Gln). This variant is present in population databases (rs140156029, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer or an unspecified cancer (PMID: 25186627, 28873162). ClinVar contains an entry for this variant (Variation ID: 141135). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000586807	SCV000567604	uncertain significance	not provided	2022-03-24	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with breast cancer and advanced cancer of unspecified type (Tung 2015, Mandelker 2017); This variant is associated with the following publications: (PMID: 28944238, 11092888, 11160897, 16879101, 20816984, 28873162, 25186627)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586807	SCV000601661	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00024 (6/24920 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)) or unspecified cancer (PMID: 28873162 (2017)). The variant has also been reported in individuals with colorectal cancer (PMID: 30267214 (2018), 28944238 (2017)). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484904	SCV000697713	uncertain significance	not specified	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.920G>A (p.Arg307Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251290 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (7.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.920G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast cancer/unspecified advanced cancer (e.g. Mandelker_2017, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. A co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA1 c.2457delC, p.Asp821fsX25; Internal testing). 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: 28944238, 28873162, 25186627). ClinVar contains an entry for this variant (Variation ID: 141135). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129507	SCV000910765	likely benign	Hereditary cancer-predisposing syndrome	2017-01-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129507	SCV002532342	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-03	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000467096	SCV004171501	uncertain significance	Familial adenomatous polyposis 2	2023-10-18	criteria provided, single submitter	clinical testing	The MUTYH c.920G>A (p.Arg307Gln) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with MUTYH-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV000467096	SCV004198854	uncertain significance	Familial adenomatous polyposis 2	2024-03-05	criteria provided, single submitter	clinical testing