Submissions for variant NM_001048174.2(MUTYH):c.160T>C (p.Ser54Pro)

gnomAD frequency: 0.00001  dbSNP: rs773198648

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218436	SCV000274756	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	The p.S82P variant (also known as c.244T>C), located in coding exon 3 of the MUTYH gene, results from a T to C substitution at nucleotide position 244. The serine at codon 82 is replaced by proline, an amino acid with similar properties. This amino acid position is well 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.
GeneDx	RCV000235580	SCV000292712	uncertain significance	not provided	2019-04-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32854451)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525881	SCV000639303	uncertain significance	Familial adenomatous polyposis 2	2024-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 82 of the MUTYH protein (p.Ser82Pro). This variant is present in population databases (rs773198648, gnomAD 0.003%). 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: 231029). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000218436	SCV000690547	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 82 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 MUTYH-related disorders in the literature. This variant has been identified in 3/251464 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235580	SCV001470570	uncertain significance	not provided	2023-02-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/251464 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been reported in individuals with breast cancer (PMIDs: 32854451 (2020) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ MUTYH)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000218436	SCV002532271	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267956	SCV002552528	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000525881	SCV004198819	uncertain significance	Familial adenomatous polyposis 2	2024-03-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000525881	SCV004838064	uncertain significance	Familial adenomatous polyposis 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 82 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251464 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.