rs121908439

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001040108.2(MLH3):c.3826T>C(p.Trp1276Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,571,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense, splice_region

Scores

Splicing: ADA: 0.00002373

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: -3.48

Publications

4 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038110465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.3826T>C	p.Trp1276Arg	missense_variant, splice_region_variant	Exon 8 of 13	ENST00000355774.7	NP_001035197.1	Q9UHC1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7 link	c.3826T>C	p.Trp1276Arg	missense_variant, splice_region_variant	Exon 8 of 13	5	NM_001040108.2	ENSP00000348020.2		Q9UHC1-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251418

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000986

AC:

AN:

1419220

Hom.:

Cov.:

AF XY:

0.0000127

AC XY:

AN XY:

708796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32580

American (AMR)

AF:

0.00

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.000101

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00000932

AC:

AN:

1073138

Other (OTH)

AF:

0.00

AC:

AN:

58988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000118

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7

Pathogenic:1Uncertain:1

Sep 07, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1276 of the MLH3 protein (p.Trp1276Arg). This variant is present in population databases (rs121908439, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancers (PMID: 12702580, 16981255). ClinVar contains an entry for this variant (Variation ID: 5564). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect MLH3 function (PMID: 18521850). 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. -

not specified

Uncertain:1

Mar 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W1276R variant (also known as c.3826T>C), located in coding exon 7 of the MLH3 gene, results from a T to C substitution at nucleotide position 3826. The tryptophan at codon 1276 is replaced by arginine, an amino acid with dissimilar properties. This variant segregated with disease in one family with colorectal cancer meeting Amsterdam criteria II; however, it co-occurred with a paternally inherited MSH2 missense variant in all four affected siblings whose tumors were microsatellite stable and demonstrated normal MSH2 protein expression on immunohistochemistry (Liu HX et al. Cancer Res., 2003 Apr;63:1894-9; Lagerstedt Robinson K et al. J. Natl Cancer Inst., 2007 Feb;99:291-9). This alteration did not segregate with disease in one Chinese family with familial esophageal cancer (Liu HX et al. World J. Gastroenterol., 2006 Sep;12:5281-6). In one study, the W1276R variant as part of the MutLγ complex showed normal protein stability and interaction with MLH1 as compared to wild type MLH3; mismatch repair efficiency of the W1276R recombinant protein was also similar to that of wild type MutLγ in vitro (Korhonen MK et al, 2008 Sep;47:803-9). This amino acid position is not well conserved in available vertebrate species, and arginine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated 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

0.070

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.0010

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.059

T;.;T

Eigen

Benign

-2.5

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.44

T;T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.038

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-2.5

N;.;N

PhyloP100

-3.5

PrimateAI

Benign

0.21

PROVEAN

Benign

1.5

N;.;N

REVEL

Uncertain

0.39

Sift

Benign

0.98

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.033

MutPred

0.67

Gain of catalytic residue at K1280 (P = 0.0101);.;Gain of catalytic residue at K1280 (P = 0.0101);

MVP

0.28

MPC

0.18

ClinPred

0.030

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.44

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.016

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over