Submissions for variant NM_001048174.2(MUTYH):c.953C>G (p.Ser318Trp)

dbSNP: rs587778538

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165499	SCV000216230	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	The p.S346W variant (also known as c.1037C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide position 1037. The serine at codon 346 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration was detected in 1/503 male breast cancer patients who had previously tested negative for BRCA1/2 mutations (Rizzolo P et al. Front Oncol, 2018 Dec;8:583). 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	RCV000203957	SCV000261495	uncertain significance	Familial adenomatous polyposis 2	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 346 of the MUTYH protein (p.Ser346Trp). This variant is present in population databases (rs587778538, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 30564557). ClinVar contains an entry for this variant (Variation ID: 185982). 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.
Counsyl	RCV000203957	SCV000792412	uncertain significance	Familial adenomatous polyposis 2	2017-06-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759877	SCV000889516	uncertain significance	not provided	2018-06-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165499	SCV001356409	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool 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 been reported in an individual affected with male breast cancer (PMID: 30564557). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 6/241834 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	RCV000759877	SCV001778064	uncertain significance	not provided	2018-10-17	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
Sema4, Sema4	RCV000165499	SCV002532197	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492662	SCV002791066	uncertain significance	Familial adenomatous polyposis 2; Gastric cancer	2022-03-15	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000203957	SCV004031236	uncertain significance	Familial adenomatous polyposis 2	2023-07-25	criteria provided, single submitter	clinical testing	The MUTYH c.1037C>G (p.Ser346Trp) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in 1 of 503 male breast cancer patients who were negative for alterations in BRCA1/2 (PMID: 30564557). To our knowledge, this variant has not been reported in individuals with MUTYH-associated polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000203957	SCV004835081	uncertain significance	Familial adenomatous polyposis 2	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tryptophan at codon 346 of the MUTYH protein. Computational prediction tool 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 been reported in an individual affected with male breast cancer (PMID: 30564557). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 4/53461 controls (PMID: 33471991). This variant has been identified in 6/241834 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.
Baylor Genetics	RCV000203957	SCV005056056	uncertain significance	Familial adenomatous polyposis 2	2024-02-01	criteria provided, single submitter	clinical testing