rs377022215

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001040108.2(MLH3):c.3539G>A(p.Arg1180His) variant causes a missense change. The variant allele was found at a frequency of 0.0000942 in 1,571,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1180G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.17

Publications

1 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 -1 ACMG points.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000995 (142/1427442) while in subpopulation MID AF = 0.000176 (1/5672). AF 95% confidence interval is 0.0000949. There are 0 homozygotes in GnomAdExome4. There are 67 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.3539G>A	p.Arg1180His	missense_variant	Exon 5 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.3539G>A	p.Arg1180His	missense_variant	Exon 5 of 13	5	NM_001040108.2	ENSP00000348020.2		Q9UHC1-1

Frequencies

GnomAD3 genomes

AF:

0.0000416

AC:

AN:

144368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000732

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:

0.0000448

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000124

AC:

AN:

250732

AF XY:

0.0000885

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000995

AC:

142

AN:

1427442

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

711234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32518

American (AMR)

AF:

0.000114

AC:

AN:

43774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.0000275

AC:

AN:

36414

South Asian (SAS)

AF:

0.000105

AC:

AN:

85634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51250

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.000111

AC:

121

AN:

1088494

Other (OTH)

AF:

0.0000856

AC:

AN:

58438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000416

AC:

AN:

144368

Hom.:

Cov.:

AF XY:

0.0000431

AC XY:

AN XY:

69620

show subpopulations

African (AFR)

AF:

0.0000514

AC:

AN:

38890

American (AMR)

AF:

0.0000732

AC:

AN:

13652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

4730

South Asian (SAS)

AF:

0.00

AC:

AN:

4618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

66926

Other (OTH)

AF:

0.00

AC:

AN:

1966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000113

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Sep 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R1180H variant (also known as c.3539G>A), located in coding exon 4 of the MLH3 gene, results from a G to A substitution at nucleotide position 3539. The arginine at codon 1180 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in the heterozygous state in a cohort of pancreatic cancer patients undergoing multigene panel testing (Young EL et al. BMC Cancer, 2018 Jun;18:697). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1180 of the MLH3 protein (p.Arg1180His). This variant is present in population databases (rs377022215, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 478037). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7

Uncertain:1

Mar 30, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MLH3-related disorder

Uncertain:1

Dec 08, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MLH3 c.3539G>A variant is predicted to result in the amino acid substitution p.Arg1180His. This variant has been reported in an individual with a personal history of pancreatic cancer (Supplemental Table 2, Young et al. 2018. PubMed ID: 29945567). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it has been reported as a variant of uncertain significance by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/478037/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;.

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.2

M;M;M

PhyloP100

6.2

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Uncertain

0.50

Sift

Benign

0.045

D;.;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.58

MVP

0.91

MPC

0.57

ClinPred

0.34

GERP RS

5.8

Varity_R

0.25

gMVP

0.63

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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rs377022215

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