rs374950566

Positions:

• chr1-45332215-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000456914.7(MUTYH):​c.800C>T​(p.Pro267Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P267S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MUTYH ENST00000456914.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 7.74

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-45332215-G-A is Pathogenic according to our data. Variant chr1-45332215-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332215-G-A is described in Lovd as [Pathogenic]. Variant chr1-45332215-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.884C>T	p.Pro295Leu	missense_variant	10/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.800C>T	p.Pro267Leu	missense_variant	10/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.884C>T	p.Pro295Leu	missense_variant	10/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.800C>T	p.Pro267Leu	missense_variant	10/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251116 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135804

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461848 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MUTYH: PM3:Strong, PM2, PS3:Moderate, PS4:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 29, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 11, 2019	- -

Familial adenomatous polyposis 2 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jul 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Feb 20, 2023	ACMG criteria used to clasify this variant:PS3, PP3_STR, PS4_MOD, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 18, 2022	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 05, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 09, 2021	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). -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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. -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;.;.;.;.;D;.;.;.;D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	.;.;.;.;.;H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-9.3	D;D;D;D;D;D;D;D;D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.84
MVP		0.99
MPC		0.55
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374950566; hg19: chr1-45797887;