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rs121912961

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000249.4(MLH1):c.350C>G(p.Thr117Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T117M) has been classified as Pathogenic.

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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000249.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37004444-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17094.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 3-37004444-C-G is Pathogenic according to our data. Variant chr3-37004444-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90178.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37004444-C-G is described in Lovd as [Pathogenic]. Variant chr3-37004444-C-G is described in Lovd as [Likely_pathogenic]. Variant chr3-37004444-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1NM_000249.4 linkuse as main transcriptc.350C>G p.Thr117Arg missense_variant 4/19 ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.350C>G p.Thr117Arg missense_variant 4/191 NM_000249.4 P1P40692-1

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
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 21, 2016This 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2019- -
Pathogenic, no assertion criteria providedresearchMayo Clinic Laboratories, Mayo Clinic-- -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 09, 2021The 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. -
Likely pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 19, 2021This 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. -
Lynch syndrome 1 Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Mar 09, 2018Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.986 -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeFeb 14, 2023This 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; API