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GeneBe

3-37025949-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_000249.4(MLH1):​c.1351A>G​(p.Thr451Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. T451I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

MLH1
NM_000249.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -1.83
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 Uncertain_significance. Variant got 0 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000249.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06475389).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1NM_000249.4 linkuse as main transcriptc.1351A>G p.Thr451Ala missense_variant 12/19 ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.1351A>G p.Thr451Ala missense_variant 12/191 NM_000249.4 P1P40692-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 11, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicApr 30, 2019- -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 28, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 451 of the MLH1 protein (p.Thr451Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 219538). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 06, 2020This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Uncertain
0.031
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
0.094
DANN
Benign
0.14
DEOGEN2
Benign
0.39
T;.;.;.;.;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.0039
N
LIST_S2
Benign
0.40
T;T;.;.;.;T
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.065
T;T;T;T;T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
0.55
N;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.81
N;N;N;N;N;N
REVEL
Uncertain
0.60
Sift
Benign
0.66
T;T;T;T;T;T
Sift4G
Benign
0.84
T;T;T;T;T;T
Polyphen
0.0
B;.;.;.;.;.
Vest4
0.16
MutPred
0.13
Loss of phosphorylation at T451 (P = 0.0394);.;.;.;.;.;
MVP
0.99
MPC
0.065
ClinPred
0.017
T
GERP RS
-2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.015
gMVP
0.14

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: rs864622145; hg19: chr3-37067440; API