rs121912961

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_ModeratePP1_ModeratePM5PM2_SupportingPP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000249.4:c.350C>G variant in MLH1 is a missense variant predicted to cause substitution of Threonin by Arginin at amino acid 117 (p.Thr117Arg). Criteria PM5 is met since p.(Thr117Arg) is a missense change at an amino acid residue where a different missense change was classified by this VCEP as pathogenic on the protein level and not due to aberrant splicing (p.Thr117Met is InSiGHT class 5). The variant is not reported in gnomAD v2.1 and once in gnomAD v4.1 (PM2_supporting). Co-segregation studies showed segragation with disease in pedigree(s) with a combined Bayes Likelihood Ratio >2.08 & ≤4.32 (PP1). The prior probability is 0.948 (PP3_moderate). The variant was detected in 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for Lynch-Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PM5, PM2_SUP, PP1, PP3, PP4 (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA009864/MONDO:0007356/115

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

15

3

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 5.83

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_pathogenic. Variant got 9 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.350C>G	p.Thr117Arg	missense_variant	4/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.350C>G	p.Thr117Arg	missense_variant	4/19	1	NM_000249.4	ENSP00000231790	P1	P40692-1

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461768

Hom.:

0

Cov.:

30

AF XY:

0.00000138

AC XY:

1

AN XY:

727188

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:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2016	This variant is denoted MLH1 c.350C>G at the cDNA level, p.Thr117Arg (T117R) at the protein level, and results in the change of a Threonine to an Arginine (ACG>AGG). This variant has been identified in at least four individuals from three Hereditary Nonpolyposis Colorectal Cancer kindreds, with studied tumors demonstrating microsatellite instability and loss of MLH1 expression on immunohistochemistry (Buerstedde 1995, Casey 2005, Hardt 2011, Buerki 2012). Functional studies have demonstrated decreased MLH1 expression and LexA binding, defective mismatch repair activity, and no or reduced dominant mutator effect, consistent with pathogenicity (Shimodaira 1998, Ellison 2001, Kondo 2003, Takahashi 2007). MLH1 Thr117Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Thr117Arg occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is located in the ATPase domain (Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MLH1 Thr117Arg to be a likely pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 19, 2021	This missense variant replaces threonine with arginine at codon 117 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has 32% of normal mismatch repair activity in vitro (PMID: 17510385) and reduced expression in yeast and cell culture (PMID: 11555625, 17510385). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8592341, 15713769, 19267393, 21404117). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 09, 2021	The p.T117R pathogenic mutation (also known as c.350C>G), located in coding exon 4 of the MLH1 gene, results from a C to G substitution at nucleotide position 350. The threonine at codon 117 is replaced by arginine, an amino acid with similar properties. This variant has been reported in multiple families affected with colon cancer meeting Amsterdam diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC) syndrome (Buerstedde JM et al. J. Med. Genet. 1995 Nov;32:909-12; Heinimann K et al Cancer. 1999 Jun 15;85(12):2512-8; Ellison AR et al. Hum Mol Genet. 2001 Sep;10:1889-900; Casey G et al. JAMA. 2005 Feb;293:799-809; Stojcev Z et al. Acta Biochim Pol. 2013 Jun;60:195-8; Ambry internal data). The p.T117R variant has also been detected in an individual meeting Bethesda criteria, with colon cancer diagnosed at 52 years and tumor studies demonstrating MSI-H and decreased MLH1 staining (less than 10%) on IHC (Hardt K et al. Fam. Cancer. 2011; 10:273-84). Furthermore, in one in vitro functional study, this alteration was shown to decrease MMR activity to 25.2% and reduce MLH1 expression to 25-75% in comparison to the wild-type; PMS2 expression was also reduced (Takahashi M et al. Cancer Res. 2007; 67:4595-604). Another functional study using a yeast two-hybrid assay also demonstrated decreased beta-galactosidase activity compared to wild-type (Kondo E et al. Cancer Res. 2003; 63:3302-8). Based on internal structural analysis, p.T117R is more disruptive to the ATPase domain of MLH1 than several pathogenic variants at the same position and nearby (Hu X et al. FEBS Lett. 2003 Jun 5;544(1-3):268-73; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome 1

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Mar 09, 2018

Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.986 -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 117 of the MLH1 protein (p.Thr117Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and Lynch syndrome (PMID: 8592341, 15713769, 21404117, 22034109). ClinVar contains an entry for this variant (Variation ID: 90178). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 11555625, 12810663). This variant disrupts the p.Thr117 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17135187, 19267393, 20233461). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

27

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.30

D

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

4.5

H;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.76

T

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.98

MutPred

0.88

Gain of MoRF binding (P = 0.0166);.;.;

MVP

0.99

MPC

0.43

ClinPred

1.0

D

GERP RS

5.1

Varity_R

0.99

gMVP

0.98

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.

Other links and lift over

dbSNP: rs63750781; hg19: chr3-37045935;