14-75048398-C-T

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.1258G>A(p.Val420Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,609,024 control chromosomes in the GnomAD database, including 181 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 0.011 ( 13 hom., cov: 33)

Exomes 𝑓: 0.014 ( 168 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.942

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=0.001824379).

BP6

Variant 14-75048398-C-T is Benign according to our data. Variant chr14-75048398-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75048398-C-T is described in Lovd as [Benign]. Variant chr14-75048398-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0109 (1656/152240) while in subpopulation NFE AF= 0.0155 (1056/68006). AF 95% confidence interval is 0.0147. There are 13 homozygotes in gnomad4. There are 825 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1656 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.1258G>A	p.Val420Ile	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.1258G>A	p.Val420Ile	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6 link	c.1258G>A	p.Val420Ile	missense_variant	Exon 2 of 12	1		ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000556257.5 link	c.1258G>A	p.Val420Ile	missense_variant	Exon 2 of 7	5		ENSP00000451540.1	G3V419

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1657

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.0114

AC:

2811

AN:

246462

Hom.:

AF XY:

0.0112

AC XY:

1496

AN XY:

133112

show subpopulations

Gnomad AFR exome

AF:

0.00248

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00841

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.00165

Gnomad FIN exome

AF:

0.0345

Gnomad NFE exome

AF:

0.0157

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0140

AC:

20329

AN:

1456784

Hom.:

168

Cov.:

AF XY:

0.0136

AC XY:

9870

AN XY:

724338

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00197

Gnomad4 ASJ exome

AF:

0.00862

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00143

Gnomad4 FIN exome

AF:

0.0339

Gnomad4 NFE exome

AF:

0.0157

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.0109

AC:

1656

AN:

152240

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

825

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0377

Gnomad4 NFE

AF:

0.0155

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.0136

Hom.:

Bravo

AF:

0.00799

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0115

AC:

1398

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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.Val420Ile variant was identified in 4 of 174 proband chromosomes (frequency: 0.023) from individuals or families with Lynch Syndrome and was present in 2 of 180 control chromosomes (frequency: 0.01) from healthy individuals (Heinonen_2003_PMID: 12800209, Taylor_2006_PMID:16885347). The variant was also identified in dbSNP (ID: rs28756982) as likely benign, ClinVar (classified as benign by Invitae and likely benign by Illumina Clinical Service Laboratory), and LOVD 3.0 (classified as both uncertain significance and benign) databases. The variant was identified in control databases in 3222 of 277842 chromosomes (37 homozygous) at a frequency of 0.011597 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 (Finnish) in 847 of 25008 chromosomes (freq: 0.03387), European (non-Finnish) in 2026 of 127558 chromosomes (freq: 0.01588), Other in 87 of 7106 chromosomes (freq: 0.01224), Ashkenazi Jewish in 86 of 10164 chromosomes (freq: 0.008461), African in 64 of 24830 chromosomes (freq: 0.002578), Latino in 63 of 34392 chromosomes (freq: 0.001832), South Asian in 48 of 29030 chromosomes (freq: 0.001653), East Asian in 1 of 19754 chromosomes (freq: 0.000051). 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.Val420 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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. -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

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. -

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

Feb 04, 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 13, 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. -

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

- -

MLH3-related disorder

Benign:1

Mar 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.4

DANN

Benign

0.52

DEOGEN2

Benign

0.084

T;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.31

T;T;T;.

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.4

N;N;.;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.31

N;.;N;N

REVEL

Benign

0.18

Sift

Benign

0.45

T;.;T;T

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.018

MPC

0.080

ClinPred

0.00068

GERP RS

3.2

Varity_R

0.028

gMVP

0.093

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