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rs63750781

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate

The NM_000249.4(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_000249.4 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.83
Variant links:
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000249.4
PM2
Very rare variant in population databases, with high coverage;
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
MLH1NM_000249.4 linkuse as main transcriptc.350C>A p.Thr117Lys missense_variant 4/19 ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.350C>A p.Thr117Lys missense_variant 4/191 NM_000249.4 P1P40692-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
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 submitterclinical testingAmbry GeneticsFeb 19, 2019The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
Cadd
Pathogenic
29
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.96
D;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.0
D;D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.92
MutPred
0.78
Loss of ubiquitination at K118 (P = 0.0261);.;.;
MVP
0.96
MPC
0.39
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.97
gMVP
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-37045935; API