Submissions for variant NM_001048174.2(MUTYH):c.83A>G (p.Asn28Ser)

gnomAD frequency: 0.00002  dbSNP: rs563275223

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131452	SCV000186436	likely benign	Hereditary cancer-predisposing syndrome	2018-09-05	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.
Color Diagnostics, LLC DBA Color Health	RCV000131452	SCV000905868	likely benign	Hereditary cancer-predisposing syndrome	2017-02-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824066	SCV000964947	uncertain significance	Familial adenomatous polyposis 2	2024-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 42 of the MUTYH protein (p.Asn42Ser). This variant is present in population databases (rs563275223, gnomAD 0.02%). This missense change has been observed in individual(s) with familial adenomatous polyposis (PMID: 23460355). ClinVar contains an entry for this variant (Variation ID: 142369). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194163	SCV001363475	uncertain significance	not specified	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.125A>G (p.Asn42Ser) results in a conservative amino acid change in 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 1.6e-05 in 251488 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.125A>G has been reported in the literature in one individual affected with MUTYH-associated Polyposis (Cruz-Correa_2013). This report does 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000824066	SCV004843484	likely benign	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV004719710	SCV005326207	uncertain significance	not provided	2024-02-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a family reported to have MUTYH Associated Polyposis (PMID: 23460355); This variant is associated with the following publications: (PMID: 23460355)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004719710	SCV005622949	uncertain significance	not provided	2024-03-14	criteria provided, single submitter	clinical testing	The MUTYH c.125A>G (p.Asn42Ser) variant has been reported in the published literature in heterozygous individuals with multiple colorectal adenomas (PMID: 23460355 (2013)) and with breast cancer (PMID: 33606809 (2021)). The frequency of this variant in the general population, 0.00025 (4/16256 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.