rs28756982

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:13

Conservation

PhyloP100: 0.942

Publications

17 publications found

Variant links:

COSMIC-nc: COSV104587306

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
intestinal polyposis syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

MLH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 238243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.1258G>A	p.Val420Ile	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.1258G>A	p.Val420Ile	missense	Exon 2 of 12	NP_055196.2	Q9UHC1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH3	ENST00000355774.7	TSL:5 MANE Select	c.1258G>A	p.Val420Ile	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6	TSL:1	c.1258G>A	p.Val420Ile	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000930871.1		c.1258G>A	p.Val420Ile	missense	Exon 2 of 13	ENSP00000600930.1

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

GnomAD2 exomes

AF:

0.0114

AC:

2811

AN:

246462

AF XY:

0.0112

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 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

African (AFR)

AF:

0.00206

AC:

AN:

33076

American (AMR)

AF:

0.00197

AC:

AN:

43694

Ashkenazi Jewish (ASJ)

AF:

0.00862

AC:

224

AN:

25988

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39656

South Asian (SAS)

AF:

0.00143

AC:

121

AN:

84902

European-Finnish (FIN)

AF:

0.0339

AC:

1805

AN:

53322

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0157

AC:

17388

AN:

1110208

Other (OTH)

AF:

0.0104

AC:

628

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1069

2137

3206

4274

5343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

644

1288

1932

2576

3220

<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:

0.0109

AC:

1656

AN:

152240

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

825

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00245

AC:

102

AN:

41554

American (AMR)

AF:

0.00216

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0377

AC:

399

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0155

AC:

1056

AN:

68006

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

170

255

340

425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0139

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Colorectal cancer, hereditary nonpolyposis, type 7 (3)

not specified (3)

Endometrial carcinoma (1)

MLH3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.4

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.084

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.4

PhyloP100

0.94

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.31

REVEL

Benign

0.18

Sift

Benign

0.45

Sift4G

Benign

0.63

Polyphen

0.0

Vest4

0.018

MPC

0.080

ClinPred

0.00068

GERP RS

3.2

Varity_R

0.028

gMVP

0.093

Mutation Taster

=283/17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over