rs63750781
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2_SupportingPM5PP3_ModeratePP5_Moderate
The NM_000249(MLH1):c.350C>A(p.Thr117Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic 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. T117M) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
MLH1
NM_000249 missense
NM_000249 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 5.83
Links
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 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_000249
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 33.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr3-37004444-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17094. Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.927
PP5
?
Variant 3:37004444-C>A is Pathogenic according to our data. Variant chr3-37004444-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1732140. Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| MLH1 | NM_000249.4 | c.350C>A | p.Thr117Lys | missense_variant | 4/19 | ENST00000231790.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | c.350C>A | p.Thr117Lys | missense_variant | 4/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomesCov.: 33
GnomAD3 genomes
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2019 | The p.T117K variant (also known as c.350C>A), located in coding exon 4 of the MLH1 gene, results from a C to A substitution at nucleotide position 350. The threonine at codon 117 is replaced by lysine, an amino acid with similar properties. This variant has been identified in an individual whose family history was suggestive of hereditary non-polyposis colorectal cancer (HNPCC) syndrome (Ambry internal data). Another alteration at the same position, p.T117R, has been reported to decrease MMR activity and reduce MLH1 and PMS2 expression (Takahashi M et al. Cancer Res. 2007; 67:4595-604). MLH1 p.T117R has also been reported in multiple families affected with colon cancer meeting Amsterdam or Bethesda diagnostic criteria for HNPCC syndrome (Buerstedde JM et al J. Med. Genet. 1995;32:909-12; Ellison A et al Hum Mol Genet. 2001 Sep 1;10(18):1889-900; Heinimann K et al Cancer. 1999 Jun 15;85(12):2512-8, Hardt K et al. Fam. Cancer 2011; 10:273-84). Based on an internal structural assessment, the p.T117K variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of ubiquitination at K118 (P = 0.0261);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.