chr14-75047786-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001040108.2(MLH3):c.1870G>C(p.Glu624Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,614,018 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0099 ( 89 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 1.23

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042276084).

BP6

Variant 14-75047786-C-G is Benign according to our data. Variant chr14-75047786-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 5560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75047786-C-G is described in Lovd as [Pathogenic]. Variant chr14-75047786-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00745 (1135/152320) while in subpopulation NFE AF= 0.0121 (823/68032). AF 95% confidence interval is 0.0114. There are 6 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.1870G>C	p.Glu624Gln	missense_variant	Exon 2 of 13	ENST00000355774.7	NP_001035197.1	Q9UHC1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MLH3	ENST00000355774.7 link	c.1870G>C	p.Glu624Gln	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6 link	c.1870G>C	p.Glu624Gln	missense_variant	Exon 2 of 12	1		ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000556257.5 link	c.1870G>C	p.Glu624Gln	missense_variant	Exon 2 of 7	5		ENSP00000451540.1	G3V419

Frequencies

GnomAD3 genomes

AF:

0.00745

AC:

1134

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.00719

GnomAD3 exomes

AF:

0.00716

AC:

1799

AN:

251246

Hom.:

AF XY:

0.00712

AC XY:

967

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00582

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.00804

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.00636

GnomAD4 exome

AF:

0.00987

AC:

14420

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00959

AC XY:

6976

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00575

Gnomad4 ASJ exome

AF:

0.00394

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00167

Gnomad4 FIN exome

AF:

0.00953

Gnomad4 NFE exome

AF:

0.0115

Gnomad4 OTH exome

AF:

0.00894

GnomAD4 genome

AF:

0.00745

AC:

1135

AN:

152320

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

528

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00771

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00641

Gnomad4 NFE

AF:

0.0121

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00689

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.00728

AC:

884

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0100

EpiControl

AF:

0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7

Uncertain:1Benign:3

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2009

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MLH3 p.Glu624Gln variant was identified in 7 of 1036 proband chromosomes (frequency: 0.00676) from individuals or families with suspected Lynch syndrome or colorectal cancer (Wu_2001_PMID: 11586295, Liu_2003_PMID: 12702580, Rohlin_2017_PMID: 27696107, & Hienonen_2003_PMID: 12800209). The variant was also identified in the following databases: dbSNP (ID: rs28756986) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as benign by Invitae with the associated phenotype of Hereditary nonpolyposis colorectal cancer type 7/MLH3-Related Lynch Syndrome; and uncertain significance by OMIM), and LOVD 3.0 (multiple entries with classifications of VUS, likely benign, and pathogenic). The variant was not identified in the Cosmic database. The variant was identified in control databases in 2120 of 282638 chromosomes (11 homozygous) at a frequency of 0.007501 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1516 of 129054 chromosomes (freq: 0.01175), European (Finnish) in 201 of 25108 chromosomes (freq: 0.008005), Other in 49 of 7218 chromosomes (freq: 0.006789), Latino in 210 of 35396 chromosomes (freq: 0.005933), Ashkenazi Jewish in 39 of 10362 chromosomes (freq: 0.003764), African in 51 of 24968 chromosomes (freq: 0.002043), South Asian in 53 of 30584 chromosomes (freq: 0.001733) and East Asian in 1 of 19948 chromosomes (freq: 0.00005). To clarify the role of the p.E624Q, in vitro functional studies were conducted transfecting wildtype and mutant MLH3 into HEK293T cells which showed no difference in protein expression, stability, localization or interaction with wildtype MLH1 (Ou_2009_PMID: 19156873). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Glu624 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;.;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.89

D;D;D;.

MetaRNN

Benign

0.0042

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;M;.;M

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

N;.;N;N

REVEL

Benign

0.19

Sift

Benign

0.043

D;.;T;D

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.99

D;D;.;D

Vest4

0.11

MVP

0.64

MPC

0.11

ClinPred

0.014

GERP RS

3.9

Varity_R

0.17

gMVP

0.38

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