chr3-37048980-A-G

Position:

chr3-37048980-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_ModerateBP6_Very_Strong

The NM_000249.4(MLH1):c.2066A>G(p.Gln689Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000306 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q689H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:17

Conservation

PhyloP100: 5.69

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000249.4

BP4

Computational evidence support a benign effect (MetaRNN=0.21073344).

BP6

Variant 3-37048980-A-G is Benign according to our data. Variant chr3-37048980-A-G is described in ClinVar as [Benign]. Clinvar id is 90016.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048980-A-G is described in Lovd as [Benign]. Variant chr3-37048980-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.2066A>G	p.Gln689Arg	missense_variant	18/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.2066A>G	p.Gln689Arg	missense_variant	18/19	1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000263

AC:

AN:

251170

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000441

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000317

AC:

464

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

230

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000381

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000197

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000341

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:17

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	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2021	Variant summary: MLH1 c.2066A>G (p.Gln689Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 253582 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (0.00028 vs 0.00071), allowing no conclusion about variant significance. c.2066A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. c.2066A>G has been reported in the literature in individuals affected with microsatellite stable colorectal, endometrioid, rectal and breast cancers but also associated with normal IHC and also found in controls (example, Hampel_2006, Barnetson_2008, Hinrichsen_2015, Pinto_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no or mild functional impairment in mismatch repair (MMR) activity associated with this variant and no effect on splicing (Hardt_2011, Hinrichsen_2015, Takahashi_2007, Tournier_2008). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=2; likely benign, n=4; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging consensus among peers supporting a neutral outcome as outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in multiple papers in HGMD, with the comments suggesting the variant is benign and possible protective. Classified in ClinVar as Benign by Expert panel (3 stars) and 3 other submitters (Invitae, Ambry, GeneDx). MaxMAF = .05% (high for disease prevalence) -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2021	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 11, 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MLH1: BP1, BS3:Moderate, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2018	This variant is associated with the following publications: (PMID: 27553368, 22736432, 21404117, 17510385, 25477341, 25637381, 22949387, 18033691, 11726306, 18561205, 18383312, 24362816, 22290698, 16885385, 30998989) -

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

Apr 25, 2023

- -

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 -

MLH1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.;.;.;.;.

Eigen

Benign

0.075

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

T;T;.;.;.;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Uncertain

0.034

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.

MutationTaster

Benign

0.98

D;D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

N;N;N;N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.33

T;T;T;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.

Vest4

0.54

MVP

0.99

MPC

0.071

ClinPred

0.034

GERP RS

5.9

Varity_R

0.19

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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