rs121912960

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP3BP6_Very_Strong

The NM_000249.4(MLH1):c.1733A>G(p.Glu578Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E578D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense, splice_region

Scores

Splicing: ADA: 0.4354

Clinical Significance

Benign reviewed by expert panel U:4B:11

Conservation

PhyloP100: 2.90

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000249.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

BP6

Variant 3-37047520-A-G is Benign according to our data. Variant chr3-37047520-A-G is described in ClinVar as [Benign]. Clinvar id is 17090.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37047520-A-G is described in Lovd as [Benign]. Variant chr3-37047520-A-G is described in Lovd as [Pathogenic]. Variant chr3-37047520-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1733A>G	p.Glu578Gly	missense_variant, splice_region_variant	16/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1733A>G	p.Glu578Gly	missense_variant, splice_region_variant	16/19	1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251238

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.000238

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727214

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:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000639

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000630

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2023	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 29, 2015	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -

not specified

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 10, 2020	Variant summary: MLH1 c.1733A>G (p.Glu578Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein, mlh1, C-terminal domain (IPR032189) of 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 0.00012 in 251238 control chromosomes, predominantly at a frequency of 0.00024 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 Lynch Syndrome (0.00012 vs 0.00071), allowing no conclusion about variant significance. c.1733A>G has been reported in the literature in individuals affected with features similar to but not fulfilling the classic diagnostic criteria associated with Lynch syndrome (example, Tanngergard_1995). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic MLH1 variant has been reported in a family with Lynch syndrome (Wagner_2003, MLH1 deletion of exons 1-13), providing additional evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function with contradictory findings across dominant mutator effect (DME) assays in yeast model systems, in-vitro MMR activity, and protein-protein interaction with hPMS2 and hMRE11 (example, Shimodaira_1998, Guerrette_1999, Kondo_2003, Ou_2007, Takahashi_2007, Ali_2012). Subsequent reports evaluating expression, stability and MMR activity in conjunction with clinical data have demonstrated no damaging effect of this variant resulting in a categorical classification as a neutral MLH1 variant (example, Vo_2005, Andersen_2012, Hinrichsen_2013). Seven 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 as benign/likely benign (n=4), and VUS (n=3). Additionally an expert panel (InSight) has classified this variant as benign before 2014. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 2016	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: Several publications in HGMD describe as nonpathogenic based on functional characterizations -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2018	This alteration is classified as likely 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 11, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 19, 2021	- -

Lynch syndrome

Uncertain:1Benign:1

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability <0.001 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 12, 2015	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2020

This variant is associated with the following publications: (PMID: 21404117, 15184898, 8521398, 18373977, 17192056, 18566915, 18383312, 19697156, 22290698, 17594722, 10037723, 17510385, 20020535, 20978114, 17312306, 15494688, 12658575, 11304573, 11474654, 10564582, 10598809, 9697702, 22753075, 15864295, 23403630, 12810663) -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;.;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;.;.;.;D

M_CAP

Benign

0.080

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Pathogenic

0.80

Sift

Benign

0.099

T;D;D;D;D;D

Sift4G

Benign

0.19

T;T;T;T;T;T

Polyphen

0.0050

B;.;.;.;.;.

Vest4

0.89

MVP

0.97

MPC

0.079

ClinPred

0.074

GERP RS

5.6

Varity_R

0.37

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.44

dbscSNV1_RF

Benign

0.60

SpliceAI score (max)

0.090

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