Submissions for variant NM_001048174.2(MUTYH):c.427A>G (p.Asn143Asp)

gnomAD frequency: 0.00001  dbSNP: rs773674701

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166145	SCV000216917	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	The p.N171D variant (also known as c.511A>G), located in coding exon 7 of the MUTYH gene, results from an A to G substitution at nucleotide position 511. The asparagine at codon 171 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457696	SCV000545800	uncertain significance	Familial adenomatous polyposis 2	2023-07-18	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 186535). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (rs773674701, gnomAD 0.007%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 171 of the MUTYH protein (p.Asn171Asp).
Counsyl	RCV000457696	SCV000800068	uncertain significance	Familial adenomatous polyposis 2	2018-05-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280570	SCV001467773	uncertain significance	not specified	2020-12-11	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.511A>G (p.Asn171Asp) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251470 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.511A>G in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000457696	SCV004198878	uncertain significance	Familial adenomatous polyposis 2	2023-08-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000457696	SCV004839672	uncertain significance	Familial adenomatous polyposis 2	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 171 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has been identified in 2/251470 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.