14-75039913-G-T

Position:

chr14-75039913-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001040108.2(MLH3):c.3568C>A(p.Gln1190Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000178 in 1,348,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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 0.000036 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense, splice_region

Scores

Splicing: ADA: 0.006586

Clinical Significance

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

Conservation

PhyloP100: 4.10

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12205157).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2 linkuse as main transcript	c.3568C>A	p.Gln1190Lys	missense_variant, splice_region_variant	5/13	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.3568C>A	p.Gln1190Lys	missense_variant, splice_region_variant	5/13	5	NM_001040108.2	ENSP00000348020	P1	Q9UHC1-1

Frequencies

GnomAD3 genomes

AF:

0.0000362

AC:

AN:

138056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000237

Gnomad SAS

AF:

0.000682

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248514

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134546

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1210874

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

612354

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000210

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000400

GnomAD4 genome

AF:

0.0000362

AC:

AN:

138056

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

66030

show subpopulations

Gnomad4 AFR

AF:

0.0000268

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000237

Gnomad4 SAS

AF:

0.000682

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The p.Q1190K variant (also known as c.3568C>A), located in coding exon 4 of the MLH3 gene, results from a C to A substitution at nucleotide position 3568. The glutamine at codon 1190 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available 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. -

Colorectal cancer, hereditary nonpolyposis, type 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 410887). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. This variant is present in population databases (rs779651509, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1190 of the MLH3 protein (p.Gln1190Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.086

T;.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

T;T;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.13

N;N;N

MutationTaster

Benign

0.77

D;D;D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.40

N;.;N

REVEL

Benign

0.17

Sift

Benign

0.49

T;.;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.019

B;B;B

Vest4

0.18

MutPred

0.52

Gain of catalytic residue at I1186 (P = 0.002);Gain of catalytic residue at I1186 (P = 0.002);Gain of catalytic residue at I1186 (P = 0.002);

MVP

0.81

MPC

0.18

ClinPred

0.15

GERP RS

4.9

Varity_R

0.077

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0066

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.020

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