chr3-37001045-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001167618.3(MLH1):​c.-426C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000125 in 1,595,500 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 Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MLH1
NM_001167618.3 5_prime_UTR_premature_start_codon_gain

Scores

4
2
1

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 3.85
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.625
PP5
Variant 3-37001045-C-T is Pathogenic according to our data. Variant chr3-37001045-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 36550.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37001045-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.298C>T p.Arg100* stop_gained Exon 3 of 19 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.298C>T p.Arg100* stop_gained Exon 3 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152094
Hom.:
0
Cov.:
32
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1443406
Hom.:
0
Cov.:
27
AF XY:
0.00000139
AC XY:
1
AN XY:
719290
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:
9.13e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152094
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
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:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:18
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:7
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 08, 2019
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 23, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 10480359, 10995807, 11606497, 15872200, 15849733, 15955785, 17267619, 17312306, 19419416, 25980754, 27601186, 27965287, 29238914); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15872200, 17312306, 17267619, 10995807, 29950348, 30382883, 34343771, 31830689, 33858029, 29758216, 30998989, 25525159, 10480359, 18415027, 25980754, 15955785, 15849733, 15235038, 15475387, 11606497, 19419416, 27601186, 27965287, 29866690, 29238914, 33087929, 33047316, 33471991) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 17, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This nonsense variant causes the premature termination of MLH1 protein synthesis. The frequency of this variant in the general population, 0.0000087 (1/114534 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 25980754 (2015), 21642682 (2011), 17453009 (2007), 17312306 (2007), 17267619 (2007), 15955785 (2005), 15872200 (2005), 15849733 (2005), 15235038 (2004), 11606497 (2001), 10995807 (2000)). Based on the available information, this variant is classified as pathogenic. -

Nov 02, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:4
Oct 14, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg100X variant in MLH1 has been reported in at least 10 individuals with Lynch syndrome and segregated with disease in at least 6 affected individuals from 2 families (Wang 1999, Samowitz 2001, Renknen 2003, Renkonen 2004, Taylor 2003 Mangold 2005, Choi 2009, Hampel 2005, Lagerstedt 2007, Peel 2000, Gylling 2007). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 36550). This nonsense variant leads to a premature termination codon at position 100, which is predicted to lead to a truncated or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PP1_Moderate. -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MLH1 p.Arg100X variant was identified in 10 of 8938 proband chromosomes from individuals with colon or gastric cancer and was absent in 146 control chromosomes (Choi 2009, Gylling 2007, Hampel 2005, Lagerstedt Robinson 2007, Mangold 2005, Peel 2000, Samowitz 2001, Taylor 2003). The variant was also identified in dbSNP (ID: rs63751221) “With pathogenic allele”, HGMD, UMD (44X), “Mismatch Repair Genes Variant Database”, and the COSMIC database. The p.Arg100X variant leads to a premature stop codon at position 100, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. Three studies showed microsatellite instability in tumours from patients positive for the variant (Gylling 2007, Hampel 2005, Samowitz 2001); Gylling (2007) also showed loss of heterozygosity of MLH1 in the tumour analysed. In addition, Lagerstedt Robinson (2007) demonstrated a loss of MLH1 protein expression in a tumour from a patient with the variant. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Aug 18, 2011
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing;curation

- -

Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: research

Coding sequence variation resulting in a stop codon -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:3
Apr 20, 2017
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 17, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 15, 2023
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2
Jan 15, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant changes 1 nucleotide in exon 3 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Sep 17, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.298C>T (p.R100*) alteration, located in exon 3 (coding exon 3) of the MLH1 gene, consists of a C to T substitution at nucleotide position 298. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 100. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation is well described in the literature and has been reported in multiple individuals and families with hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (Taylor, 2003; Renkonen, 2004; Hampel, 2005; Mangold, 2005; Lagerstedt Robinson, 2007; Gylling, 2007; Choi, 2009; Bonadona, 2011; Stojcev, 2013; Kamiza, 2015; Guindalini, 2015; Azizi, 2018). In one study, this variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Breast Cancer Association, 2021). Of note, this alteration is also designated as "100 Arg>stop (CGA>TGA)," R100X, and p.Arg100X in published literature. Based on the available evidence, this alteration is classified as pathogenic. -

Lynch-like syndrome Pathogenic:1
Jul 01, 2019
Constitutional Genetics Lab, Leon Berard Cancer Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg100*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10480359, 11606497, 14512394, 15235038, 15872200, 17312306). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 36550). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.88
D
Vest4
0.93
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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: rs63751221; hg19: chr3-37042536; COSMIC: COSV51614696; API