NM_001048174.2:c.1007G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP6

The NM_001048174.2(MUTYH):​c.1007G>T​(p.Arg336Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R336H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

MUTYH
NM_001048174.2 missense

Scores

1
15
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.58

Publications

0 publications found
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]
MUTYH Gene-Disease associations (from GenCC):
  • familial adenomatous polyposis 2
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
  • colorectal cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
  • familial ovarian cancer
    Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
  • hereditary breast carcinoma
    Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 1-45331756-C-A is Benign according to our data. Variant chr1-45331756-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1789506.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MUTYHNM_001048174.2 linkc.1007G>T p.Arg336Leu missense_variant Exon 12 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.1007G>T p.Arg336Leu missense_variant Exon 12 of 16 1 NM_001048174.2 ENSP00000407590.2 Q9UIF7-6
ENSG00000288208ENST00000671898.1 linkn.1595G>T non_coding_transcript_exon_variant Exon 16 of 21 ENSP00000499896.1 A0A5F9ZGZ0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Oct 17, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method: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; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1
Mar 19, 2020
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R364L variant (also known as c.1091G>T), located in coding exon 12 of the MUTYH gene, results from a G to T substitution at nucleotide position 1091. The arginine at codon 364 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
.;.;.;.;.;T;.;.;.;T;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.97
.;D;.;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Uncertain
0.58
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.7
.;.;.;.;.;M;.;.;.;.;.
PhyloP100
4.6
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-4.3
D;D;D;D;D;D;D;D;D;.;D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;.;D
Sift4G
Uncertain
0.0040
D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.59, 0.84, 0.75
.;.;.;.;.;P;P;.;P;.;.
Vest4
0.34
MutPred
0.41
.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0256);.;.;
MVP
0.91
MPC
0.51
ClinPred
0.99
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.66
Mutation Taster
=74/26
polymorphism

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

Other links and lift over

dbSNP: rs587780741; hg19: chr1-45797428; API