14-75048943-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001040108.2(MLH3):c.713A>C(p.Tyr238Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,613,242 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y238C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 4 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.18

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

colorectal cancer, hereditary nonpolyposis, type 7
Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

MLH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02066508).

BP6

Variant 14-75048943-T-G is Benign according to our data. Variant chr14-75048943-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238252.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000499 (76/152260) while in subpopulation AMR AF = 0.000589 (9/15288). AF 95% confidence interval is 0.000307. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.713A>C	p.Tyr238Ser	missense_variant	Exon 2 of 13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MLH3	ENST00000355774.7 link	c.713A>C	p.Tyr238Ser	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6 link	c.713A>C	p.Tyr238Ser	missense_variant	Exon 2 of 12	1		ENSP00000370355.3
MLH3	ENST00000556257.5 link	c.713A>C	p.Tyr238Ser	missense_variant	Exon 2 of 7	5		ENSP00000451540.1
MLH3	ENST00000553263.1 link	c.*226A>C		downstream_gene_variant		2		ENSP00000451192.1

Frequencies

GnomAD3 genomes

AF:

0.000499

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000816

AC:

204

AN:

249962

AF XY:

0.000872

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.000320

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.000450

AC:

657

AN:

1460982

Hom.:

Cov.:

AF XY:

0.000493

AC XY:

358

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33374

American (AMR)

AF:

0.000359

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.0151

AC:

394

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000198

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000123

AC:

137

AN:

1111724

Other (OTH)

AF:

0.00133

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000499

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41482

American (AMR)

AF:

0.000589

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68042

Other (OTH)

AF:

0.00143

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000832

Hom.:

Bravo

AF:

0.000536

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jun 25, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Colorectal cancer, hereditary nonpolyposis, type 7

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

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.Tyr238Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs144707485) and in ClinVar (classified as uncertain significance by Illumina Clinical Services Laboratory for Lynch syndrome and likely benign by Invitae for MLH3-Related Lynch syndrome). The variant was identified in control databases in 209 of 281376 chromosomes (3 homozygous) at a frequency of 0.000743 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: Ashkenazi Jewish in 154 of 10324 chromosomes (freq: 0.01492), Other in 14 of 7150 chromosomes (freq: 0.001958), Latino in 11 of 35232 chromosomes (freq: 0.000312), European (non-Finnish) in 26 of 128544 chromosomes (freq: 0.000202), South Asian in 3 of 30418 chromosomes (freq: 0.000099), African in 1 of 24738 chromosomes (freq: 0.00004), but was not observed in the East Asian or European (Finnish) populations. Although the p.Tyr238 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. 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 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.

MLH3-related disorder

Benign:1

Jun 14, 2024

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

Uncertain

0.42

BayesDel_addAF

Benign

0.0043

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

D;.;.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

T;T;T;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.5

M;M;.;M

PhyloP100

2.2

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.8

D;.;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

D;.;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Vest4

0.49

ClinPred

0.11

GERP RS

4.5

Varity_R

0.68

gMVP

0.77

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over