Submissions for variant NM_001048174.2(MUTYH):c.991C>A (p.Pro331Thr)

gnomAD frequency: 0.00003  dbSNP: rs587782773

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132303	SCV000187388	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-08	criteria provided, single submitter	clinical testing	The p.P359T variant (also known as c.1075C>A), located in coding exon 12 of the MUTYH gene, results from a C to A substitution at nucleotide position 1075. The proline at codon 359 is replaced by threonine, an amino acid with highly similar properties. This variant has been reported in the literature as an undefined rare variant that was identified in combination with another MUTYH mutation in a patient who had colorectal cancer diagnosed under the age of sixty with at least two affected family members; however, phase for the two variants (whether in cis or trans) was not determined (Cheadle JP and Sampson JR. DNA Repair (Amst.) 2007 Mar; 6(3):274-9). This alteration was also identified in an individual in conjunction with the p.Y179C MUTYH pathogenic variant; however, phase for the two variants was not determined. Furthermore, the individual in which these two MUTYH variants were identified met Amsterdam I criteria for Lynch syndrome, but had normal mismatch repair (MMR) function by tumor testing which demonstrated microsatellite stability and/or normal expression of the four MMR proteins (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). Of note, this alteration is also designated as c.1033C>A (p.P345T) in published literature. 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.
Counsyl	RCV000411922	SCV000487368	uncertain significance	Familial adenomatous polyposis 2	2016-08-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411922	SCV000545747	uncertain significance	Familial adenomatous polyposis 2	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 359 of the MUTYH protein (p.Pro359Thr). This variant is present in population databases (rs587782773, gnomAD 0.003%). This missense change has been observed in individual(s) with MUTYH-related disease (PMID: 17161978, 17581577, 28944238). This variant is also known as P345T. ClinVar contains an entry for this variant (Variation ID: 142860). 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.
Color Diagnostics, LLC DBA Color Health	RCV000132303	SCV000690497	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 359 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 performed for this variant. This variant has been reported in one individual affected with colorectal cancer in conjunction with another MUTYH variant (PMID: 28944238). This variant has been identified in 4/280336 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780503	SCV000917808	uncertain significance	not specified	2022-09-29	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1075C>A (p.Pro359Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248940 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1075C>A has been reported in the literature in individuals affected with MUTYH-Associated Polyposis (DeRycke_2017). This report does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001582608	SCV001819443	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1033C>A p.(Pro345Thr); This variant is associated with the following publications: (PMID: 30719162, 19725997, 27153395, 17581577, 20618354, 28944238, 17161978)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001582608	SCV002011072	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483271	SCV002796937	uncertain significance	Familial adenomatous polyposis 2; Gastric cancer	2022-05-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001582608	SCV003800329	uncertain significance	not provided	2022-02-28	criteria provided, single submitter	clinical testing	The MUTYH c.1075C>A; p.Pro359Thr variant (rs587782773), also known as P345T, is reported in the literature in individuals affected with MUTYH-associated polyposis (Cheadle 2007, DeRycke 2017, Morak 2010). At least two individuals had a second MUTYH variant, but phase was not determined (DeRycke 2017, Morak 2010). This variant is also reported in ClinVar (Variation ID: 142860) and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 359 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.857). However, given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Cheadle JP and Sampson JR. MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing. DNA Repair (Amst). 2007 Mar 1;6(3):274-9. PMID: 17161978. DeRycke MS et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Mol Genet Genomic Med. 2017 Jul 23;5(5):553-569. PMID: 28944238. Morak M et al. MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet. 2010 Oct;78(4):353-63. PMID: 20618354.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000411922	SCV004171510	uncertain significance	Familial adenomatous polyposis 2	2023-10-24	criteria provided, single submitter	clinical testing	The MUTYH c.1075C>A (p.Pro359Thr) missense change has a maximum subpopulation frequency of 0.0031% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in one individual with colorectal cancer who also harbored the p.Tyr179Cys pathogenic variant, however phase for the variants was not determined (PMID: 28944238). This individual met the Amsterdam Criteria I for Lynch syndrome, but tumor profiling demonstrated normal mismatch repair function (microsatellite stable) and/or normal expression of four MMR proteins encoded by MLH1, MSH2, MSH6, and PMS2 in the tumor (PMID: 28944238). This variant is also known as c.1033C>A (p.P345T) in published literature. 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	RCV000411922	SCV004835014	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 359 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 performed for this variant. This variant has been reported in one individual affected with colorectal cancer in conjunction with another MUTYH variant (PMID: 28944238). This variant has been identified in 4/280336 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	RCV000411922	SCV005056024	uncertain significance	Familial adenomatous polyposis 2	2024-03-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780503	SCV005090576	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing