3-37000965-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000249.4(MLH1):​c.218T>G​(p.Leu73Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L73L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MLH1
NM_000249.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.56
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 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 3-37000965-T-G is Pathogenic according to our data. Variant chr3-37000965-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MLH1NM_000249.4 linkuse as main transcriptc.218T>G p.Leu73Arg missense_variant 3/19 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.218T>G p.Leu73Arg missense_variant 3/191 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 06, 2023This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22692065]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22692065]. -
Muir-Torré syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinMar 11, 2022ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP3 supporting -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 01, 2022For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 22692065). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 42192). This missense change has been observed in individuals with Lynch syndrome and constitutional mismatch repair deficiency syndrome (PMID: 22692065; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 73 of the MLH1 protein (p.Leu73Arg). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 23, 2015The p.L73R variant (also known as c.218T>G), located in coding exon 3 of the MLH1 gene, results from a T to G substitution at nucleotide position 218. The leucine at codon 73 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a homozygous state in a male of Polynesian ancestry whose clinical history was consistent with constitutional mismatch repair deficiency (CMMR-D) . This individual developed glioblastoma multiforme (3 years) and T-cell lymphoblastic lymphoma (5.5 years); he was also noted to have near complete agenesis of the corpus callosum, interhemispheric and intracerebral cysts, and right subcortical and periventricular heterotopia and multiple cafe-au-lait spots. The maternal family history was also positive for colorectal cancer (Baas AF et al. Eur. J. Hum. Genet. 2013 Jan; 21(1):55-61). This amino acid position is well conserved through mammals. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Mismatch repair cancer syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.86
Gain of disorder (P = 0.0273);
MVP
0.99
MPC
0.47
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.95
gMVP
0.92

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514684; hg19: chr3-37042456; API