rs28937870

Variant summary

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

The NM_001040108.2(MLH3):c.70C>G(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q24H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 10.0

Variant links:

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]

MLH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2 linkuse as main transcript	c.70C>G	p.Gln24Glu	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7 linkuse as main transcript	c.70C>G	p.Gln24Glu	missense_variant	2/13	5	NM_001040108.2	P1	Q9UHC1-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251448

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727240

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:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

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	Invitae	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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.17

Cadd

Uncertain

Dann

Uncertain

0.97

DEOGEN2

Uncertain

0.44

T;.;.;T;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;.;D;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.73

D;D;D;D;D;D

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.5

M;M;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

N;.;N;N;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0070

D;.;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;.;.

Polyphen

1.0

D;D;.;D;.;.

Vest4

0.65

MutPred

0.68

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

0.89

MPC

0.49

ClinPred

0.80

GERP RS

5.5

Varity_R

0.87

gMVP

0.58

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over