chr3-37000970-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000249.4(MLH1):​c.223A>G​(p.Ile75Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,444,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.67
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MLH1NM_000249.4 linkuse as main transcriptc.223A>G p.Ile75Val missense_variant 3/19 ENST00000231790.8 NP_000240.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.223A>G p.Ile75Val missense_variant 3/191 NM_000249.4 ENSP00000231790 P1P40692-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1444734
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
719936
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.12e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Muir-Torré syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMMay 20, 2023The observed missense c.223A>G(p.Ile75Val) variant in MLH1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ile75Val variant is absent in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain significance. The amino acid change p.Ile75Val in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ile at position 75 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. Multiple line of computational evidence (Polyphen - probably Damaging, SIFT - Damaging, and MutationTaster - disease causing) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 04, 2023In 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 820939). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the MLH1 protein (p.Ile75Val). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 01, 2019The p.I75V variant (also known as c.223A>G), located in coding exon 3 of the MLH1 gene, results from an A to G substitution at nucleotide position 223. The isoleucine at codon 75 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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
Benign
0.13
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.91
N
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.51
MutPred
0.57
Loss of ubiquitination at K70 (P = 0.1459);
MVP
0.85
MPC
0.20
ClinPred
0.88
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.72
gMVP
0.44

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: rs1060500701; hg19: chr3-37042461; API