Submissions for variant NM_001048174.2(MUTYH):c.356A>G (p.Asn119Ser)

gnomAD frequency: 0.00003  dbSNP: rs771641237

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165758	SCV000216502	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	The p.N147S variant (also known as c.440A>G), located in coding exon 5 of the MUTYH gene, results from an A to G substitution at nucleotide position 440. The asparagine at codon 147 is replaced by serine, an amino acid with highly similar properties. This amino acid position is poorly 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	RCV000228615	SCV000285949	uncertain significance	Familial adenomatous polyposis 2	2024-12-15	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 147 of the MUTYH protein (p.Asn147Ser). This variant is present in population databases (rs771641237, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 186207). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985860	SCV001134478	uncertain significance	not provided	2019-05-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165758	SCV001357387	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 147 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251476 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	RCV000985860	SCV002558208	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002485025	SCV002793964	uncertain significance	Familial adenomatous polyposis 2; Gastric cancer	2024-06-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235085	SCV003934741	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.440A>G (p.Asn147Ser) 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 1.6e-05 in 251476 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.440A>G in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26689913). Six ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000228615	SCV004198886	uncertain significance	Familial adenomatous polyposis 2	2024-01-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000228615	SCV004839794	uncertain significance	Familial adenomatous polyposis 2	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 147 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251476 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.