rs140342925

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_001048174.2(MUTYH):​c.650G>T​(p.Arg217Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MUTYH
NM_001048174.2 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.14
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001048174.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-45332446-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 1-45332445-C-A is Pathogenic according to our data. Variant chr1-45332445-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2733895.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr1-45332445-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MUTYHNM_001048174.2 linkc.650G>T p.Arg217Leu missense_variant Exon 9 of 16 ENST00000456914.7 NP_001041639.1 Q9UIF7-6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MUTYHENST00000456914.7 linkc.650G>T p.Arg217Leu missense_variant Exon 9 of 16 1 NM_001048174.2 ENSP00000407590.2 Q9UIF7-6
ENSG00000288208ENST00000671898.1 linkn.1238G>T non_coding_transcript_exon_variant Exon 13 of 21 ENSP00000499896.1 A0A5F9ZGZ0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Oct 05, 2024
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R245L variant (also known as c.734G>T), located in coding exon 9 of the MUTYH gene, results from a G to T substitution at nucleotide position 734. The arginine at codon 245 is replaced by leucine, an amino acid with dissimilar properties. Another variant at the same codon, p.R245H (c.734G>A), has been reported in both the homozygous and compound heterozygous state in multiple individuals with colon polyposis and/or colorectal cancer (Aceto G et al. Hum. Mut. 2005 Oct;26:394; Russell AM et al. Int. J. Cancer. 2006 Apr;118:1937-40; Piccioli P et al. Clin. Chem. 2006 Apr;52:739-43; Olschwang S et al. Genet. Test. 2007;11:315-20; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1975-85; Morak M et al. Clin Genet, 2010 Oct;78:353-63; Win AK et al. Gastroenterology. 2014 May;146:1208-11.e1-5; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97; Kacerovska D et al. Am. J. Dermatopathol. 2016 Dec;38:915-92; Ricci MT et al. J Hum Genet, 2017 Feb;62:309-315; Viel A et al. EBioMedicine, 2017 Jun;20:39-49; Yanus GA et al. Clin. Genet. 2018 May;93:1015-1021; Sutcliffe EG et al. Fam Cancer, 2019 04;18:203-209; Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial adenomatous polyposis 2 Uncertain:1
Jun 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 245 of the MUTYH protein (p.Arg245Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adenomatous polyposis (PMID: 17081686). This variant is also known as R231L. 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: 17081686). This variant disrupts the p.Arg245 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16134147, 16557584, 19732775, 23108399, 24444654, 26446593). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
.;.;.;.;.;D;.;.;.;T;.;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
.;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
.;.;.;.;.;H;.;.;.;.;.;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-6.6
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;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
0.99, 0.99
.;.;.;.;.;D;D;.;D;.;.;.
Vest4
0.99
MutPred
0.95
.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0152);.;.;.;
MVP
0.99
MPC
0.54
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45798117; API