Submissions for variant NM_001048174.2(MUTYH):c.752A>G (p.Asn251Ser)

dbSNP: rs587778534

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223375	SCV000276291	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	The p.N279S variant (also known as c.836A>G), located in coding exon 10 of the MUTYH gene, results from an A to G substitution at nucleotide position 836. The asparagine at codon 279 is replaced by serine, an amino acid with highly similar properties. This alteration was detected in a multiple colorectal adenoma cohort and interpreted as a variant of unknown significance [designated as c.794AG p.Asn265Ser] (Olschwang S et al. Genet. Test., 2007;11:315-20). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000223375	SCV000685674	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 279 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 been observed in trans with a known MUTYH pathogenic variant in an individual affected with MUTYH-associated polyposis (PMID: 27145315). This variant has also been observed in an individual affected with multiple colorectal adenomas (PMID: 17949294). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001220277	SCV001392257	pathogenic	Familial adenomatous polyposis 2	2023-10-26	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 279 of the MUTYH protein (p.Asn279Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer and/or colorectal polyposis (PMID: 17949294, 21520333; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.794A>G (p.Asn265Ser). ClinVar contains an entry for this variant (Variation ID: 232218). 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. This variant disrupts the p.Asn279 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been observed in individuals with MUTYH-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800559	SCV002046633	uncertain significance	not provided	2021-02-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001220277	SCV004198925	uncertain significance	Familial adenomatous polyposis 2	2023-07-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001220277	SCV004843239	uncertain significance	Familial adenomatous polyposis 2	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 279 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 been observed in trans with a known MUTYH pathogenic variant in an individual affected with MUTYH-associated polyposis (PMID: 27145315). This variant has also been observed in an individual affected with multiple colorectal adenomas (PMID: 17949294). This variant has not been identified 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.