rs201541505

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000249.4(MLH1):c.1040C>A(p.Thr347Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. 2/3 splice prediction tools predicting alterations to 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. T347I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0025 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 missense, splice_region

Scores

Splicing: ADA: 0.9916

Clinical Significance

Benign reviewed by expert panel U:3B:13

Conservation

PhyloP100: 7.23

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.

BP6

Variant 3-37025638-C-A is Benign according to our data. Variant chr3-37025638-C-A is described in ClinVar as [Benign]. Clinvar id is 89629.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37025638-C-A is described in Lovd as [Benign]. Variant chr3-37025638-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1040C>A	p.Thr347Asn	missense_variant, splice_region_variant	12/19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.1040C>A	p.Thr347Asn	missense_variant, splice_region_variant	12/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

116394

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00112

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000434

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000547

AC:

AN:

182724

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

101458

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00246

AC:

2056

AN:

835610

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

968

AN XY:

420194

show subpopulations

Gnomad4 AFR exome

AF:

0.00330

Gnomad4 AMR exome

AF:

0.000431

Gnomad4 ASJ exome

AF:

0.00117

Gnomad4 EAS exome

AF:

0.00174

Gnomad4 SAS exome

AF:

0.00134

Gnomad4 FIN exome

AF:

0.000207

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000240

AC:

AN:

116424

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

AN XY:

53878

show subpopulations

Gnomad4 AFR

AF:

0.0000347

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000560

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000434

Gnomad4 NFE

AF:

0.000280

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000101

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000660

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2019	Variant summary: MLH1 c.1040C>A (p.Thr347Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 206178 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.3e-05 vs 0.00071), allowing no conclusion about variant significance. c.1040C>A has been reported in the literature in at-least one proband affected with colorectal cancer (Thompson_2013). This report(s) does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additionally, it was reported in a patient with sporadic etiology for colorectal cancer as evidenced by BRAF mutation positivity, high MSI, and a negative MLH1 and PMS2 staining by IHC (van der Klift_2016). BRAF mutation and MLH1 promoter hypermethylation have been reported as strong predictors of a negative germline MMR mutational status (Parsons_2012, PMID 22368298). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Additionally, one submission indicates the variant co-occurred with a pathogenic PMS2 variant (variant not indicated). In addition, an expert panel submitter, InSiGHT, and another submitter (evaluation before 2014) have classified the variant as benign. Therefore, based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 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: This variant is in the second base of exon 12 (of 19 exons). This variant is present in ExAC and gnomAD at a MaxMAF of 0.01% (15 alleles). It is classified in ClinVar as Benign by Ambry and an expert panel (InSiGHT - 3 stars) and as VUS by Invitae and GeneDx. It has not been reported in affected individuals but was seen in the Invitae database in a patient who had another PMS2 variant that was likely to explain disease. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MLH1: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2018	This variant is denoted MLH1 c.1040C>A at the cDNA level, p.Thr347Asn (T347N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as benign based on a multifactorial model that incorporates in silico models and segregation within families; however, this data is not available for independent review (Thompson 2013, Thompson 2014). MLH1 Thr347Asn was observed at an allele frequency of 0.013% (14/101,232) in individuals of European ancestry in large population cohorts (Lek 2016). MLH1 Thr347Asn is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Thr347Asn is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 26, 2020	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 13, 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	Oct 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 14, 2016	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Feb 19, 2024

According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): Posterior probability Thompson et al., 2013/InSiGHT: 0.0002, BS1 (strong benign): gnomAD all 0.007275%, in EUR 0.01384% (cut off VCEP >0,01% BS1) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;.;.;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;D;.;.;.;D

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.61

D;D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Benign

0.073

T;D;D;D;D;D

Sift4G

Benign

0.12

T;D;D;D;D;T

Polyphen

0.60

P;.;.;.;.;.

Vest4

0.59

MVP

0.88

MPC

0.094

ClinPred

0.39

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.73

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