14-75046760-A-G

Variant names:

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.2896T>C(p.Ser966Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,614,142 control chromosomes in the GnomAD database, including 341 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S966T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 31 hom., cov: 32)

Exomes 𝑓: 0.017 ( 310 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.373

Publications

20 publications found

Variant links:

COSMIC-nc: COSV104587495

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=0.0019047856).

BP6

Variant 14-75046760-A-G is Benign according to our data. Variant chr14-75046760-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0115 (1751/152338) while in subpopulation SAS AF = 0.0352 (170/4828). AF 95% confidence interval is 0.0309. There are 31 homozygotes in GnomAd4. There are 851 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 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.2896T>C	p.Ser966Pro	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.2896T>C	p.Ser966Pro	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.2896T>C	p.Ser966Pro	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6	TSL:1	c.2896T>C	p.Ser966Pro	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000930871.1		c.2896T>C	p.Ser966Pro	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1754

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0156

AC:

3912

AN:

251224

AF XY:

0.0178

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00677

Gnomad ASJ exome

AF:

0.0234

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0167

AC:

24355

AN:

1461804

Hom.:

310

Cov.:

AF XY:

0.0178

AC XY:

12916

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33480

American (AMR)

AF:

0.00776

AC:

347

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

563

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39696

South Asian (SAS)

AF:

0.0420

AC:

3625

AN:

86252

European-Finnish (FIN)

AF:

0.00556

AC:

297

AN:

53414

Middle Eastern (MID)

AF:

0.0369

AC:

213

AN:

5766

European-Non Finnish (NFE)

AF:

0.0164

AC:

18227

AN:

1111944

Other (OTH)

AF:

0.0169

AC:

1018

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1412

2824

4236

5648

7060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.0115

AC:

1751

AN:

152338

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

851

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00241

AC:

100

AN:

41568

American (AMR)

AF:

0.00993

AC:

152

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0352

AC:

170

AN:

4828

European-Finnish (FIN)

AF:

0.00415

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0149

AC:

1017

AN:

68046

Other (OTH)

AF:

0.0175

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

186

278

371

464

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:

0.0145

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0170

AC:

146

ExAC

AF:

0.0159

AC:

1927

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0185

EpiControl

AF:

0.0201

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Colorectal cancer, hereditary nonpolyposis, type 7 (3)

not provided (3)

Endometrial carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.53

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.078

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

-0.37

PrimateAI

Benign

0.26

PROVEAN

Benign

1.6

REVEL

Benign

0.13

Sift

Benign

0.97

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.028

MPC

0.13

ClinPred

0.00068

GERP RS

1.3

PromoterAI

0.0048

Neutral

(source)

Varity_R

0.039

gMVP

0.16

Mutation Taster

=299/1

polymorphism (auto)

(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