rs28756992

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.2533A>G(p.Ser845Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,184 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 32 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 114 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.182

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=0.0028146803).

BP6

Variant 14-75047123-T-C is Benign according to our data. Variant chr14-75047123-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 220674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2259/152354) while in subpopulation AFR AF= 0.0316 (1315/41584). AF 95% confidence interval is 0.0302. There are 32 homozygotes in gnomad4. There are 1084 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2259 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.2533A>G	p.Ser845Gly	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.2533A>G	p.Ser845Gly	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6 link	c.2533A>G	p.Ser845Gly	missense_variant	Exon 2 of 12	1		ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000556257.5 link	c.2533A>G	p.Ser845Gly	missense_variant	Exon 2 of 7	5		ENSP00000451540.1	G3V419
MLH3	ENST00000555671.1 link	n.79A>G		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0148

AC:

2258

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0317

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00949

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.0277

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00788

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0109

AC:

2746

AN:

251264

Hom.:

AF XY:

0.0116

AC XY:

1579

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.0306

Gnomad AMR exome

AF:

0.00610

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.0122

Gnomad SAS exome

AF:

0.0280

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00735

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.00982

AC:

14362

AN:

1461830

Hom.:

114

Cov.:

AF XY:

0.0102

AC XY:

7442

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0349

Gnomad4 AMR exome

AF:

0.00639

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.0101

Gnomad4 SAS exome

AF:

0.0267

Gnomad4 FIN exome

AF:

0.00155

Gnomad4 NFE exome

AF:

0.00833

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.0148

AC:

2259

AN:

152354

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1084

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0316

Gnomad4 AMR

AF:

0.00948

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.0102

Gnomad4 SAS

AF:

0.0280

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00788

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.00918

Hom.:

Bravo

AF:

0.0158

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.0322

AC:

142

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.0116

AC:

1410

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MLH3 p.Ser845Gly variant was identified in 5 of 934 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer and was also present in 8 of 994 control chromosomes (frequency: 0.008) from healthy individuals (de Jong_2004_PMID:15193445). The variant was identified in dbSNP (ID: rs28756992), ClinVar (classified as likely benign by Illumina and as benign by Invitae for Lynch syndrome) and LOVD 3.0 (classified as a VUS) but was not identified in Cosmic. The variant was identified in control databases in 3189 of 282666 chromosomes (38 homozygous) at a frequency of 0.011282 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: African in 791 of 24898 chromosomes (freq: 0.03177), South Asian in 856 of 30612 chromosomes (freq: 0.02796), East Asian in 240 of 19952 chromosomes (freq: 0.01203), Other in 76 of 7214 chromosomes (freq: 0.01054), European (non-Finnish) in 950 of 129064 chromosomes (freq: 0.007361), Latino in 217 of 35438 chromosomes (freq: 0.006123), Ashkenazi Jewish in 22 of 10368 chromosomes (freq: 0.002122), and European (Finnish) in 37 of 25120 chromosomes (freq: 0.001473). The p.Ser845 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 30, 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. -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Endometrial carcinoma

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.29

DANN

Benign

0.61

DEOGEN2

Benign

0.092

T;.;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.52

T;T;T;.

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.69

N;N;.;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.2

N;.;N;N

REVEL

Benign

0.20

Sift

Benign

0.57

T;.;T;T

Sift4G

Benign

0.95

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.047

MPC

0.091

ClinPred

0.0026

GERP RS

-7.2

Varity_R

0.034

gMVP

0.18

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