rs28756981

Positions:

chr14-75048965-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001040108.2(MLH3):c.691A>C(p.Lys231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,613,400 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 18 hom., cov: 33)

Exomes 𝑓: 0.017 ( 271 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.16

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039312243).

BP6

Variant 14-75048965-T-G is Benign according to our data. Variant chr14-75048965-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 220781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75048965-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0129 (1960/152328) while in subpopulation NFE AF= 0.0193 (1310/68026). AF 95% confidence interval is 0.0184. There are 18 homozygotes in gnomad4. There are 970 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1960 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2 linkuse as main transcript	c.691A>C	p.Lys231Gln	missense_variant	2/13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7 linkuse as main transcript	c.691A>C	p.Lys231Gln	missense_variant	2/13	5	NM_001040108.2	ENSP00000348020	P1	Q9UHC1-1
MLH3	ENST00000380968.6 linkuse as main transcript	c.691A>C	p.Lys231Gln	missense_variant	2/12	1		ENSP00000370355		Q9UHC1-2
MLH3	ENST00000556257.5 linkuse as main transcript	c.691A>C	p.Lys231Gln	missense_variant	2/7	5		ENSP00000451540

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1960

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0232

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0121

AC:

3016

AN:

249362

Hom.:

AF XY:

0.0122

AC XY:

1647

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.00291

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.00938

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000394

Gnomad FIN exome

AF:

0.0249

Gnomad NFE exome

AF:

0.0186

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.0172

AC:

25160

AN:

1461072

Hom.:

271

Cov.:

AF XY:

0.0168

AC XY:

12199

AN XY:

726786

show subpopulations

Gnomad4 AFR exome

AF:

0.00234

Gnomad4 AMR exome

AF:

0.00563

Gnomad4 ASJ exome

AF:

0.00808

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000709

Gnomad4 FIN exome

AF:

0.0235

Gnomad4 NFE exome

AF:

0.0202

Gnomad4 OTH exome

AF:

0.0142

GnomAD4 genome

AF:

0.0129

AC:

1960

AN:

152328

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

970

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00380

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0232

Gnomad4 NFE

AF:

0.0193

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0173

Hom.:

Bravo

AF:

0.0120

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0192

AC:

165

ExAC

AF:

0.0123

AC:

1488

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0177

EpiControl

AF:

0.0169

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2020	This alteration is classified as 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. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;.;.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.093

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.77

T;T;T;.

MetaRNN

Benign

0.0039

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.5

L;L;.;L

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.20

Sift

Benign

0.26

T;.;T;T

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.53

P;B;.;P

Vest4

0.10

MPC

0.14

ClinPred

0.015

GERP RS

4.5

Varity_R

0.21

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over