3-37040251-C-T

Variant names:

• chr3-37040251-C-T
• rs63750192
• NM_000249.4:c.1624C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.1624C>T​(p.Gln542*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q542Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.70
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37040251-C-T is Pathogenic according to our data. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040251-C-T is described in CliVar as Pathogenic. Clinvar id is 89809.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1624C>T	p.Gln542*	stop_gained	Exon 14 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1624C>T	p.Gln542*	stop_gained	Exon 14 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Nov 28, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MLH1 c.1624C>T at the cDNA level and p.Gln542Ter (Q542X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least two individuals with hereditary non-polyposis colorectal cancer (HNPCC), one of whom had a tumor that showed microsatellite instability (MSI-H) and lack of MLH1 protein expression by immunohistochemistry (Tournier 2004, Bonnet 2012). We consider this variant to be pathogenic. -

Jan 04, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Jul 21, 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. -

Lynch syndrome Pathogenic:1

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 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 21, 2024

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.Gln542*) 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: 15024732, 22480969). ClinVar contains an entry for this variant (Variation ID: 89809). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 06, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q542* pathogenic mutation (also known as c.1624C>T), located in coding exon 14 of the MLH1 gene, results from a C to T substitution at nucleotide position 1624. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This pathogenic mutation has been reported in several families diagnosed with HNPCC/Lynch syndrome (Tournier I et al. Hum Mutat. 2004 Apr;23(4):379-84; Bonadona V et al. JAMA. 2011 Jun 8;305(22):2304-10). This alteration has also been reported in a family with Turcot syndrome where the proband was diagnosed with colon cancer at age 44 and with a glioblastoma at age 62. The glioblastoma showed a loss of MLH1 on IHC (Lebrun C et al. Eur J Neurol. 2007 Apr;14(4):470-2). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.7
Vest4		0.99
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs63750192; hg19: chr3-37081742;