rs63751022

Variant names:

• chr3-37050523-G-A
• rs63751022
• NM_000249.4:c.2141G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-37050523-G-A
• chr3-37050523-G-C
• chr3-37050523-G-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.2141G>A​(p.Trp714*) 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 (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 9.76
• Publications: 11 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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 96 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37050523-G-A is Pathogenic according to our data. Variant chr3-37050523-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 90068.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.2141G>A	p.Trp714*	stop_gained	Exon 19 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2141G>A	p.Trp714*	stop_gained	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000107 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Jul 06, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MLH1 c.2141G>A (p.Trp714X) variant results in a premature termination codon, predicted to cause a truncation of C-terminal domain, a known mechanisms for disease. The functional studies demonstrated that hMLH1-hMRE11 interaction was dramatically decreased by p.Trp714X, and truncated protein lacks MMR activity. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.2179_2182delCACA/p.His727fsX55). This variant has been reported in numerous Lynch Syndrome patients and is absent in 121240 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

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 with functional domain -

May 13, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp714X variant in MLH1 has been reported in 4 individuals with Lynch syndrome and segregated with disease in 7 affected individuals from one family (Hutter 1996, Fu 2013, Lagerstedt-Robinson 2016, Martin-Morales 2018). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 90068). This nonsense variant leads to a premature termination codon at position 714. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies provide some evidence that this variant does impact protein function (Takahashi 2007). This variant was classified as Pathogenic on Sep 05, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID SCV000106549.2).In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PM4, PP1_Strong, PS3_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 23, 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 19 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes defective PMS2 interaction (PMID: 12810663) and loss of mismatch repair activity (PMID: 9697702, 17510385). This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 21642682, 23640085, 27601186, 30256826). This variant has been shown to segregate with disease in a large Lynch syndrome family (PMID: 8863153). 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. -

Nov 26, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W714* pathogenic mutation (also known as c.2141G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2141. This changes the amino acid from a tryptophan to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 43 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in numerous families with Lynch syndrome (Hutter P et al. J. Med. Genet. 1996 Aug;33(8):636-40; Sheng JQ et al. Chin. J. Dig. Dis. 2006;7(4):197-205; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Takahashi M et al. Cancer Res. 2007 May;67(10):4595-604; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36(5):2823-2835; Martin-Morales L et al. PLoS One, 2018 Sep;13:e0203885). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Jul 25, 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. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Mar 03, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Pathogenic:1

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 43 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Observed in several unrelated patients from different ethnic backgrounds with Lynch-related cancers in published literature, some of which showing tumor studies consistent with pathogenic variants in this gene (Froggatt 1996, Kondo 2003, Sheng 2006, Bonadona 2011, Martin-Morales 2018); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: inability to induce dominant mutator effect, loss of mismatch repair activity, and decreased protein expression (Shimodaira 1998, Takahashi 2007); Classified as pathogenic by a well-established clinical consortium and/or database (ClinVar); This variant is associated with the following publications: (PMID: 8863153, 25504677, 12810663, 30256826, 19931546, 25345868, 27601186, 15322516, 11093816, 8880570, 28514183, 17510385, 9697702, 17054581, 21642682, 23640085, 31830689, 9833759) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 19, 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.Trp714*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the MLH1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 8863153, 30256826). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90068). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MLH1 function (PMID: 9697702, 12810663, 17510385). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys732*) have been determined to be pathogenic (PMID: 10422993, 10923051, 12799449, 16338176, 20533529, 25197397; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	44
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.34	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.97	T
PhyloP100		9.8
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
MVP		0.98
ClinPred		0.98	D
GERP RS		5.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs63751022; hg19: chr3-37092014; COSMIC: COSV51622963; COSMIC: COSV51622963;