Submissions for variant NM_001048174.2(MUTYH):c.1397T>C (p.Phe466Ser)

gnomAD frequency: 0.00001  dbSNP: rs1394044603

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001011808	SCV001172175	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The p.F494S variant (also known as c.1481T>C), located in coding exon 15 of the MUTYH gene, results from a T to C substitution at nucleotide position 1481. The phenylalanine at codon 494 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001536926	SCV001753742	uncertain significance	not provided	2021-03-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003467598	SCV004199406	uncertain significance	Familial adenomatous polyposis 2	2023-01-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003467598	SCV004634604	uncertain significance	Familial adenomatous polyposis 2	2024-03-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 494 of the MUTYH protein (p.Phe494Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 819336). 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. 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.
All of Us Research Program, National Institutes of Health	RCV003467598	SCV004841921	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 494 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 2/272334 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.