rs529008617

Positions:

• chr1-45331529-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000456914.7(MUTYH):​c.1130C>T​(p.Pro377Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000682 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P377S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: MUTYH ENST00000456914.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:2
• Conservation: PhyloP100: 7.17

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 18 ACMG points.

• PM1: In a strand (size 11) in uniprot entity MUTYH_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000456914.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 1-45331529-G-A is Pathogenic according to our data. Variant chr1-45331529-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 142604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331529-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-45331529-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1214C>T	p.Pro405Leu	missense_variant	13/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1130C>T	p.Pro377Leu	missense_variant	13/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1214C>T	p.Pro405Leu	missense_variant	13/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1130C>T	p.Pro377Leu	missense_variant	13/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000719 AC: 18 AN: 250510 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000711 AC: 104 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.0000715 AC XY: 52 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:8 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Pro405Leu variant in MUTYH has been reported in the homozygous or compound heterozygous state in >20 individuals with autosomal recessive MUTYH-related attenuated familial adenomatous polyposis (FAP) or associated cancers (Nielsen 2005, Kanter-Smoler 2006, Aretz 2006, Vogt 2009), and was found to segregate with disease in at least 7 relatives from multiple families (Vogt 2009, Kanter-Smoler 2006). This variant has been suggested to be a Dutch founder mutation (Nielsen 2005). This variant has also been reported in ClinVar (Variation ID: 142604). This variant has been identified in 16/126332 European chromosomes by the Genome Aggregation Database (ExAC, http://exac.broadinstitute.org; dbSNP rs529008617); however, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Pro405Leu variant may impact protein function (Kundu 2009, Goto 2010, Shinmura 2012, Komine 2015). Computational prediction tools and conservation analysis suggest that the p.Pro405Leu variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-related FAP in an autosomal recessive manner based upon segregation studies and functional evidence. ACMG/AMP criteria applied: PM3_VS, PS4, PP1_S, PP3, PS3_P -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant classified as Pathogenic and reported on 04-24-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2022	Variant summary: MUTYH c.1214C>T (p.Pro405Leu) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250510 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (7.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1214C>T has been widely reported in the literature as a Dutch founder mutation in multiple biallelic homozygous and compound heterozygous individuals affected with MUTYH-Associated Polyposis (example, Jones_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Komine_2009). The most pronounced variant effect results in a functionally defective Base Excision Repair (BER) activity in a MutY-Deficient E. coli Complementation Assay. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 405 of the MUTYH protein (p.Pro405Leu). This variant is present in population databases (rs529008617, gnomAD 0.01%). This missense change has been observed in individuals with MUTYH-associated polyposis (PMID: 16140997, 16557584, 16616356, 19732775). It is commonly reported in individuals of Dutch ancestry (PMID: 17161978, 20191381). This variant is also known as 1172C>T, P391L, and P377L. ClinVar contains an entry for this variant (Variation ID: 142604). 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: 19836313, 20848659, 23322991, 25820570). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces proline with leucine at codon 405 in the nudix hydrolase domain of the MUTYH protein. This variant is also known as c.1172C>T (p.Pro391Leu) based on an alternative transcript (NM_001048171). 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 showed severely reduced glycosylase and bacterial complementation activities (PMID: 19836313, 20848659, 25820570). This variant has been reported in many individuals and families affected with MUTYH-associated polyposis (MAP) (PMID: 16140997, 16557584, 16616356, 17674103, 19732775, 20191381, 20618354, 25938944, 28944238) and is known to be a common disease-causing mutation in the Dutch population (PMID: 16140997, 18172263, 22297469). This variant has been identified in 20/281904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Common in the Dutch population -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 13, 2018	The MUTYH c.1172C>T (p.Pro391Leu) is a missense variant. Across a selection of the available literature, the p.Pro391Leu variant has been found in 19 individuals affected with polyposis, including six in a homozygous state and 13 in a compound heterozygous state (Kanter-Smoler G et al. 2006; Nielsen et al. 2005; Aretz et al. 2006; Middeldorp et al. 2008). The variant was absent from 424 control alleles and is reported at a frequency of 0.000183 in the European (non-Finnish) population of the Exome Aggregation Consortium (Kanter-Smoler G et al. 2006; Aretz et al. 2006). Functional studies demonstrated the variant resulted in severely impaired glycosylase activity (Kundu et al. 2009; Goto et al. 2010) and mutation suppression compared to wild type (Kundu et al. 2009; Shinmura et al. 2012; Komine et al. 2015). The Pro391 residue is conserved across species and is located in a functionally important domain (Kundu et al. 2009). Based on the collective data, the p.Pro391Leu variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	Published functional studies demonstrate a damaging effect: variant associated with severely impaired glycosylase activity and severely suppressed oxidative mutagenesis (Kundu et al., 2009; Goto et al., 2010; Shinmura et al., 2012; Komine et al., 2015); 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: 23322991, 25820570, 25938944, 23007840, 17674103, 22297469, 19031083, 28152038, 32088803, 32782288, 19836313, 20848659, 19732775, 16140997, 27153395, 28873162, 28790112, 28944238, 27631816, 20191381, 16557584, 16616356, 20618354, 18506705, 17489848, 25937855, 23605219, 31589614, 30787465, 30604180, 34680242, 23108399, 30291343) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2017	- -

Carcinoma of colon Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Pro405Leu (Alias: p.Pro391Leu) variant has been previously reported in the literature in 30/1730 proband chromosomes, of whom 23 were homozygous or compound heterozygous for this variant or a second pathogenic variant, consistent with the autosomal recessive inheritance of the MUTYH-associated polyposis coli. The variant was not observed in 424 controls (Aretz 2006, Bouquen 2007, Goto_2010, Kanter-Smoler 2006, Kundu 2009, Middeldorp 2008, Nielsen 2005, Vogt 2009). The MYH Pro405/391 residue is conserved across mammals, and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the variant may impact the protein. Although this information is not predictive enough to assume pathogenicity, functional studies analyzing the adenine glycosylase activity have shown that the variant showed compromised enzymatic activity that was 30–40% of the wild type enzyme. (Goto 2010, Kundu 2009). In summary, based on the above information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2022	The p.P405L pathogenic mutation (also known as c.1214C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1214. The proline at codon 405 is replaced by leucine, an amino acid with similar properties. This mutation was reported in a Dutch cohort of polyposis patients who had previously tested negative for APC mutations; it was seen in 14% of the patients with biallelic MUTYH mutations, including two probands who were homozygous for p.P405L (Nielsen M et al. J. Med. Genet. 2005 Sep;42:e54). In another study examining the extracolonic tumor spectrum in patients with MUTYH-polyposis, authors observed this mutation in 23 out of 376 patients, including four individuals who were homozygous carriers of the p.P405L mutation and 19 compound heterozygotes (Vogt S et al. Gastroenterology 2009 Dec;137:1976-85.e1-10). This alteration has also been identified in a 40-year old male with 100 adenomas in a compound heterozygous state (Morak M et al. Clin. Genet. 2010 Oct;78:353-63). Functional analysis of this alteration has revealed compromised adenine glycosylase activity that was 30-40% of the activity of the wildtype enzyme (Kundu S et al. DNA Repair (Amst.) 2009 Dec;8:1400-10). In addition, several other studies have found this alteration to be functionally defective (Goto M et al. Hum. Mutat. 2010 Nov;31:E1861-74; Shinmura K et al. World J. Gastroenterol. 2012 Dec;18:6935-42; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.P391L (c.1172C>T) in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
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 405 in the nudix hydrolase domain of the MUTYH protein. This variant is also known as c.1172C>T (p.Pro391Leu) based on an alternative transcript (NM_001048171). 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 showed severely reduced glycosylase and bacterial complementation activities (PMID: 19836313, 20848659, 25820570). This variant has been reported in many individuals and families affected with MUTYH-associated polyposis (MAP) (PMID: 16140997, 16557584, 16616356, 17674103, 19732775, 20191381, 20618354, 25938944, 28944238) and is known to be a common disease-causing mutation in the Dutch population (PMID: 16140997, 18172263, 22297469). This variant has been identified in 20/281904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

B lymphoblastic leukemia lymphoma, no ICD-O subtype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Apr 04, 2017

This is a missense alteration in which a C is replaced by a T at coding nucleotide 1214 and is predicted to change a Proline to a Leucine at amino acid codon 405. Classification criteria: PS3, PM2, PM3, PP3, PP5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;.;.;.;.;D;.;.;.;.;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.8	.;.;.;.;.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.1	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;D;D;.;.;D;.
Vest4		0.89
MVP		0.98
MPC		0.56
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.94

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: rs529008617; hg19: chr1-45797201;