Submissions for variant NM_001048174.2(MUTYH):c.504G>C (p.Glu168Asp)

gnomAD frequency: 0.00002  dbSNP: rs587781645

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129775	SCV000184584	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	clinical testing	The p.E196D variant (also known as c.588G>C), located in coding exon 8 of the MUTYH gene, results from a G to C substitution at nucleotide position 588. The glutamic acid at codon 196 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported as variant of uncertain significance in 2/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000484778	SCV000565254	uncertain significance	not provided	2015-08-05	criteria provided, single submitter	clinical testing	This variant is denoted MUTYH c.588G>C at the cDNA level, p.Glu196Asp (E196D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Glu196Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. MUTYH Glu196Asp occurs at a position that is conserved in mammals and is not located in a known functional domain (Ruggieri 2013, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MUTYH Glu196Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000539493	SCV000639344	uncertain significance	Familial adenomatous polyposis 2	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 196 of the MUTYH protein (p.Glu196Asp). This variant is present in population databases (rs587781645, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 141306). 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.
Color Diagnostics, LLC DBA Color Health	RCV000129775	SCV000690589	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 196 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 reported for this variant. This variant has been reported in individuals referred for hereditary cancer screening (PMID: 31159747). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 5/251470 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.
GeneKor MSA	RCV000129775	SCV000822076	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000539493	SCV000837770	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375560	SCV001572440	uncertain significance	not specified	2021-04-01	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.588G>C (p.Glu196Asp) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of 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 2e-05 in 251470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.588G>C has been reported in the literature in individuals screened for hereditary cancer (e.g. Tsaousis_2019). 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. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000129775	SCV002532305	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-23	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484778	SCV002774650	uncertain significance	not provided	2021-08-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000539493	SCV004198893	uncertain significance	Familial adenomatous polyposis 2	2023-08-17	criteria provided, single submitter	clinical testing