rs63750449

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM5PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.1853A>C(p.Lys618Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,614,148 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K618A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0049 ( 21 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:18O:1

Conservation

PhyloP100: 7.33

Variant links:

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

MLH1 links:

MLH1 (HGNC:):

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-37047638-GAA-GGC is described in Lovd as [Pathogenic].

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.028957754).

BP6

Variant 3-37047640-A-C is Benign according to our data. Variant chr3-37047640-A-C is described in ClinVar as [Benign]. Clinvar id is 89906.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37047640-A-C is described in Lovd as [Likely_benign]. Variant chr3-37047640-A-C is described in Lovd as [Benign]. Variant chr3-37047640-A-C is described in Lovd as [Pathogenic]. Variant chr3-37047640-A-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0039 (594/152306) while in subpopulation AMR AF= 0.00928 (142/15294). AF 95% confidence interval is 0.00804. There are 2 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1853A>C	p.Lys618Thr	missense_variant	16/19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1853A>C	p.Lys618Thr	missense_variant	16/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00391

AC:

595

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00930

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00553

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00347

AC:

873

AN:

251414

Hom.:

AF XY:

0.00342

AC XY:

465

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00572

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00487

AC:

7113

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

3417

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00467

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000786

Gnomad4 NFE exome

AF:

0.00591

Gnomad4 OTH exome

AF:

0.00402

GnomAD4 genome

AF:

0.00390

AC:

594

AN:

152306

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.00928

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00551

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.00400

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00341

AC:

414

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00581

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:18Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:6

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -
Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 03, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The p.Lys618Thr variant in MLH1 is classified as benign because it has been identified in 0.57% (735/129116, 2 homozygotes) chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is a common haplotype with c.1852A>G. ACMG/AMP Criteria applied: BA1. -

not provided

Uncertain:1Benign:2Other:1

not provided, no classification provided	literature only	Harris Lab, University of Minnesota	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MLH1: PP3, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 22, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	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, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 10, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Colorectal cancer, non-polyposis

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 22, 2023

- -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Lynch syndrome 1

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Lynch syndrome

Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability <0.001 -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;.;.;.;D

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.029

T;T;T;T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.91

MVP

0.97

MPC

0.41

ClinPred

0.074

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.83

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