Submissions for variant NM_001048174.2(MUTYH):c.800C>T (p.Pro267Leu)

gnomAD frequency: 0.00001  dbSNP: rs374950566

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164625	SCV000215289	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	The p.P295L pathogenic mutation (also known as c.884C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 884. The proline at codon 295 is replaced by leucine, an amino acid with similar properties. This mutation has been described in multiple patients with adenomatous polyposis who were homozygous for this mutation or compound heterozygous for this and another pathogenic MUTYH alteration (Lejeune S et al. Hum. Mutat., 2006 Oct;27:1064; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10; Jones N et al. Gastroenterology, 2009 Aug;137:489-94, 494.e1; quiz 725-6; Morak M et al. Clin. Genet., 2010 Oct;78:353-63; Croitoru ME et al. J Surg Oncol, 2007 May;95:499-506; Yanus GA et al. Clin. Genet., 2018 May;93:1015-1021). In vitro functional studies demonstrate DNA binding activity and base excision repair activity are severely defective (Ali M et al. Gastroenterology 2008 Aug; 135(2):499-507; Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this alteration is also described as p.P281L (c.842C>T) in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx	RCV000235921	SCV000293494	pathogenic	not provided	2023-08-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: defective DNA binding capability, compromised base excision activity, and near absent glycosylase activity (Ali et al., 2008; Brinkmeyer et al., 2015; Komine et al., 2015); Observed in both the homozygous and compound heterozygous state in individuals affected with MUTYH Associated Polyposis (Jones et al., 2009; Nielsen et al., 2009; Vogt et al., 2009; Morak et al., 2010); 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; This variant is associated with the following publications: (PMID: 25820570, 18534194, 30604180, 34637943, 16941501, 19032956, 19394335, 20618354, 23507534, 26377631, 19732775, 31159747, 32231684, 30291343, 32283892, 34426522, 31589614, 30787465, 29406563, 35089076, 33980423, 34271781, 35238777, 35418818, 17219385, 36368126, 35734982, 35261632, 11092888, 11160897, 16879101, 20816984, 37065479, 37453313, 16557584)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456980	SCV000545714	pathogenic	Familial adenomatous polyposis 2	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 295 of the MUTYH protein (p.Pro295Leu). This variant is present in population databases (rs374950566, gnomAD 0.004%). This missense change has been observed in individual(s) with polyposis and/or colorectal cancer (PMID: 19732775; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 185242). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 18534194, 25820570, 26377631). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164625	SCV000685679	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 295 in the FeS cluster domain 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). Functional studies have shown that this variant causes deficient mismatch repair and DNA-binding (PMID: 18534194, 26377631). This variant has been reported in the homozygous state or compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID: 16557584, 16941501, 17219385, 19032956, 20618354, 29406563, 35238777). This variant has also been reported in individuals affected with colorectal cancer (PMID: 32658311, 33980423, 34271781) and breast cancer (PMID: 33471991, 33980423, 35089076, 35734982, 36368126; DOI: 10.14744/ejmo.2022.88057). This variant has been identified in 3/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Counsyl	RCV000456980	SCV000796726	likely pathogenic	Familial adenomatous polyposis 2	2017-12-22	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000164625	SCV000821747	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-09	criteria provided, single submitter	clinical testing	This missense mutation results in the substitution of amino acid Proline with Leucine at codon 295 of the MUTYH protein. The proline residue is highly conserved and there is physiochemical difference between proline and Leucine (Grantham Score 98). This variant is present at low frequency in population databases (rs374950566, ExAC <0.01%). Additionally, it has been reported in the literature in individuals affected with polyposis and/or colorectal cancer (PMID: 19732775, PMID: 19394335, PMID: 19032956, PMID: 17219385, PMID: 16557584). Experimental studies have confirmed the disrupting effect of this variant in the protein function (PMID: 25820570, PMID: 26377631). The mutation database ClinVar contains entries for this variant (Variation ID: 185242).
CeGaT Center for Human Genetics Tuebingen	RCV000235921	SCV001248081	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	MUTYH: PM3:Strong, PM2, PS3:Moderate, PS4:Moderate
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000235921	SCV001449728	likely pathogenic	not provided	2019-02-11	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000235921	SCV001762178	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164625	SCV002532338	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235921	SCV002760323	likely pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000456980	SCV004021287	pathogenic	Familial adenomatous polyposis 2	2023-07-26	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000456980	SCV004042770	pathogenic	Familial adenomatous polyposis 2	2023-02-20	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PS3, PP3_STR, PS4_MOD, PM2_SUP
Baylor Genetics	RCV000456980	SCV004198973	pathogenic	Familial adenomatous polyposis 2	2024-01-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000456980	SCV004841020	pathogenic	Familial adenomatous polyposis 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 295 in the FeS cluster domain 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). Functional studies have shown that this variant causes deficient mismatch repair and DNA-binding (PMID: 18534194, 26377631). This variant has been reported in the homozygous state or compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID: 16557584, 16941501, 17219385, 19032956, 20618354, 29406563, 35238777). This variant has also been reported in individuals affected with colorectal cancer (PMID: 32658311, 33980423, 34271781) and breast cancer (PMID: 33471991, 33980423, 35089076; DOI: 10.14744/ejmo.2022.88057). This variant has been identified in 3/251116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000235921	SCV005199296	pathogenic	not provided	2022-08-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353603	SCV000592700	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MUTYH p.Pro295Leu variant has been reported in 5 probands with multiple adenoma polyposis (MAP) (Lejeune 2006, Jones 2009). All of these probands were homozygous or compound heterozygous. The variant has also been found in a homozygous state in an individual with MAP (Jones 2009). The MUTYH p.Pro295Leu variant was identified in 8 of 1126 proband chromosomes (frequency: 0.007 from individuals or families with multiple adenoma polyposis (MAP) and was not identified in 100 control chromosomes from healthy individuals (Aretz 2006, Croitoru 2007, Lejeune 2006, Vogt 2009); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in HGMD, “InSiGHT Colon Cancer Database” and UMD (4X as a causal variant). The variant was identified by the Exome Variant Server project in 1 of 4405 African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Pro295 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the p.Pro295Leu variant may impact the protein. Lejeune (2006) notes that this variant is located in an important functional domain involved in substrate binding and catalysis, and an in vitro functional study demonstrated that the p.Pro295Leu variant was severely defective in both glycosylase and DNA binding (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554252	SCV001774841	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000235921	SCV001809199	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000235921	SCV001919254	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235921	SCV001954416	pathogenic	not provided		no assertion criteria provided	clinical testing