rs28937870
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001040108.2(MLH3):āc.70C>Gā(p.Gln24Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000014 ( 0 hom. )
Consequence
MLH3
NM_001040108.2 missense
NM_001040108.2 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 20 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.70C>G | p.Gln24Glu | missense_variant | 2/13 | ENST00000355774.7 | NP_001035197.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.70C>G | p.Gln24Glu | missense_variant | 2/13 | 5 | NM_001040108.2 | ENSP00000348020.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152130Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251448Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135898
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461884Hom.: 0 Cov.: 35 AF XY: 0.0000206 AC XY: 15AN XY: 727240
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152130Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74322
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:2
Uncertain significance, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 17, 2023 | 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. Experimental studies have shown that this missense change does not substantially affect MLH3 function (PMID: 18521850, 19156873). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5558). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11586295). This variant is present in population databases (rs28937870, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 24 of the MLH3 protein (p.Gln24Glu). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2023 | The p.Q24E variant (also known as c.70C>G), located in coding exon 1 of the MLH3 gene, results from a C to G substitution at nucleotide position 70. The glutamine at codon 24 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was identified in an individual whose colorectal tumor demonstrated low microsatellite instability and normal MLH1/MSH2/MSH6 protein expression on immunochemistry (IHC) (Wu Y et al. Nat Genet, 2001 Oct;29:137-8). This alteration was not identified in a cohort of 30 colorectal cancer patients or 174 cancer-free controls (Hienonen T et al. Int J Cancer, 2003 Aug;106:292-6). Functional assays for p.Q24E demonstrated protein expression, subcellular localization and interaction with MLH1 to be similar to wild type MLH3 (Ou J et al. Genes Chromosomes Cancer, 2009 Apr;48:340-50). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;.;N;N;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;D;D;D
Sift4G
Uncertain
D;D;D;D;.;.
Polyphen
D;D;.;D;.;.
Vest4
MutPred
Gain of catalytic residue at I19 (P = 0.0831);Gain of catalytic residue at I19 (P = 0.0831);Gain of catalytic residue at I19 (P = 0.0831);Gain of catalytic residue at I19 (P = 0.0831);Gain of catalytic residue at I19 (P = 0.0831);Gain of catalytic residue at I19 (P = 0.0831);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at