Submissions for variant NM_001048174.2(MUTYH):c.773G>A (p.Gly258Glu)

gnomAD frequency: 0.00001  dbSNP: rs730881833

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160754	SCV000211408	pathogenic	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired DNA glycosylase activity (Yanaru-Fujisawa et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28533537, 25931827, 32761968, 25820570, 25892863, 24799981, 23605219, 28251689, 21235684, 28087410, 19953527, 25151137, 17703316, 29330641, 30604180, 30833417, 31360874, 32888815, 32521533, 31742824, 32973888, 30787465, 11092888, 11160897, 18422726)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000191933	SCV000267404	likely pathogenic	Familial adenomatous polyposis 2	2016-03-18	criteria provided, single submitter	reference population
Ambry Genetics	RCV000221854	SCV000278100	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	The p.G286E pathogenic mutation (also known as c.857G>A) is located in coding exon 10 of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 857. The glycine at codon 286 is replaced by glutamic acid, an amino acid with very few similar properties. A Chinese patient with colon cancer diagnosed at age 40 and his sister with colon polyps were found to have this variant in conjunction with another MUTYH alteration, p.Q267* (Zhang JX et al. World J. Gastroenterol. 2015 Apr; 21(14):4136-49). This alteration was reported in a Korean male diagnosed with rectal cancer at age 39 in addition to 36 polyps and it was seen in conjunction with MUTYH p.Q260* in a Japanese patient with 100-200 polyps (Kim DW et al. Int J Colorectal Dis. 2007 Oct;22(10):1173-8; Takao M et al. Int. J. Clin. Oncol. 2018 Jun;23:497-503). This alteration was also reported in conjunction with MUTYH p.S332S in a Chinese patient with pancreatic cancer diagnosed at age 45 and a history of four colorectal adenomatous polyps; her family history was significant for a brother diagnosed with colorectal cancer at age 54 and a total of 30 adenomatous polyps, a sister with multiple colon polyps, and father diagnosed with pancreatic cancer (Thibodeau ML et al. Cold Spring Harb Mol Case Stud. 2019 04;5:). In another study, this alteration was identified in the homozygous state in an individual from Japan diagnosed with adenomatous polyposis as well as five gastric carcinomas and a functional assay demonstrated impaired glycoylase activity (Yanaru-Fujisawa R et al. Clin Genet. 2008 Jun;73(6):545-53). In another functional study, this alteration had mutation suppression levels similar to wild type, but defective glycosylation levels (Komine K et al. Hum. Mutat. 2015 Jul;36(7):704-11). In addition, this variant was detected in the homozygous state in multiple individuals with polyposis by our laboratory (Ambry internal data). Of note, this alteration was previously designated as p.G272E in the literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000191933	SCV000639360	pathogenic	Familial adenomatous polyposis 2	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 286 of the MUTYH protein (p.Gly286Glu). This variant is present in population databases (rs730881833, gnomAD 0.02%). This missense change has been observed in individual(s) with polyposis, colon cancer, and rectal cancer (PMID: 17703316, 18422726, 25892863, 29330641; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.815G>A p.G272E. ClinVar contains an entry for this variant (Variation ID: 182691). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MUTYH function (PMID: 18422726, 25820570). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000221854	SCV000685675	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 286, in an FeS cluster of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting results with one complementation of E. coli DNA damage repair (PMID: 25820570) while another study reported impaired DNA repair (PMID: 18422726). This variant has been reported in compound heterozygous individuals affected with MUTYH-associated polyposis (PMID: 17703316, 18422726, 25892863, 28251689, 28533537, 29330641) or pancreatic adenocarcinoma (PMID: 30833417). This variant has also been reported in individuals affected with breast cancer (PMID: 32761968). This variant has been identified in 7/250874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191933	SCV000917807	likely pathogenic	Familial adenomatous polyposis 2	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The MUTYH c.857G>A (p.Gly286Glu) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study, Yanaru-Fuhisawa_2008, supports these predictions with the observation that the variant impedes DNA glycosylase activity. This variant is absent in 246004 control chromosomes. Multiple publications cite the variant in affected individuals including one pt, who was homozygous for the variant (Yanaru-Fuhisawa_2008) and presented with rectal cancer and colorectal polyposis. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160754	SCV001134488	pathogenic	not provided	2019-01-25	criteria provided, single submitter	clinical testing	This variant has been reported as homozygous and compound heterozygous in multiple individuals with colorectal cancer and/or polyposis in the published literature (PMID: 29330641 (2018), 28533537 (2017), 25892863 (2015), 18422726 (2008)). 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 disease causing and damaging. Experimental studies have yielded conflicting results regarding the functional impact of this variant (PMID: 25820570 (2015), 18422726 (2008)). Based on the available information, this variant is classified as pathogenic.
Revvity Omics, Revvity	RCV000191933	SCV002017834	likely pathogenic	Familial adenomatous polyposis 2	2019-05-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160754	SCV004042431	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MUTYH: PM2, PS3:Moderate, PS4:Moderate, PP3
Baylor Genetics	RCV000191933	SCV004198847	pathogenic	Familial adenomatous polyposis 2	2024-03-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000191933	SCV004843206	likely pathogenic	Familial adenomatous polyposis 2	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 286, in an FeS cluster of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting results with one complementation of E. coli DNA damage repair (PMID: 25820570) while another study reported impaired DNA repair (PMID: 18422726). This variant has been reported in compound heterozygous individuals affected with MUTYH-associated polyposis (PMID: 17703316, 18422726, 25892863, 28251689, 28533537, 29330641) or pancreatic adenocarcinoma (PMID: 30833417). This variant has also been reported in individuals affected with breast cancer (PMID: 32761968). This variant has been identified in 7/250874 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796056	SCV005417023	pathogenic	Familial adenomatous polyposis 2; Gastric cancer		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PM3_VeryStrong+PP1
GeneReviews	RCV000191933	SCV000246164	not provided	Familial adenomatous polyposis 2		no assertion provided	literature only	Found in Japanese & Korean populations
Laboratory for Genotyping Development, RIKEN	RCV003162678	SCV002758145	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research