Submissions for variant NM_001048174.2(MUTYH):c.229G>A (p.Asp77Asn)

gnomAD frequency: 0.00005  dbSNP: rs587780746

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123149	SCV000166452	uncertain significance	Familial adenomatous polyposis 2	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 105 of the MUTYH protein (p.Asp105Asn). This variant is present in population databases (rs587780746, gnomAD 0.007%). This missense change has been observed in individual(s) with sporadic colorectal cancer (PMID: 16140997, 16408224). This variant is also known as c.271G>A and p.Asp91Asn. ClinVar contains an entry for this variant (Variation ID: 135986). 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. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570, 26694661). 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.
Ambry Genetics	RCV000131617	SCV000186635	likely benign	Hereditary cancer-predisposing syndrome	2022-09-28	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000609799	SCV000712552	uncertain significance	not specified	2020-04-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759161	SCV000888313	uncertain significance	not provided	2017-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131617	SCV000911195	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 105 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant protein (also known as p.Asp77Asn and p.Asp91Asn in the literature) exhibits similar DNA glycosylase activity and ability in mutation suppression compared to the wild-type protein (PMID: 25820570, 26694661). This variant has been detected in heterozygosity without a known second mutation in at least one individual affected with colorectal cancer and polyposis (PMID: 16140997, 16408224). This variant has also been identified in 9/282862 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.
GeneDx	RCV000759161	SCV001768496	uncertain significance	not provided	2022-07-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect (Komine et al., 2015; Shinmura et al., 2016); Observed in individuals with a personal or family history of colorectal cancer and/or polyps (Nielsen et al., 2005; Niessen et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Asp91Asn); This variant is associated with the following publications: (PMID: 16408224, 16140997, 25820570, 26694661)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000759161	SCV002011192	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131617	SCV002532276	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-26	criteria provided, single submitter	curation
Baylor Genetics	RCV000123149	SCV004198936	uncertain significance	Familial adenomatous polyposis 2	2024-02-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123149	SCV004837898	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 105 of the MUTYH protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant protein (also known as p.Asp77Asn and p.Asp91Asn in the literature) exhibits similar DNA glycosylase activity and ability in mutation suppression compared to the wild-type protein (PMID: 25820570, 26694661). This variant has been detected in heterozygosity without a known second mutation in at least one individual affected with colorectal cancer and polyposis (PMID: 16140997, 16408224). This variant has also been identified in 9/282862 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000609799	SCV005090664	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000759161	SCV001925971	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000759161	SCV001955799	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759161	SCV001964431	uncertain significance	not provided		no assertion criteria provided	clinical testing