NM_000249.4(MLH1):c.67G>T (p.Glu23Ter) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001258081.2

Allele description [Variation Report for NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)]

NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)

Other names:

p.E23*:GAA>TAA

HGVS:

NC_000003.12:g.36993614G>T
NG_007109.2:g.5265G>T
NG_008418.1:g.4691C>A
NM_000249.4:c.67G>TMANE SELECT
NM_001167617.3:c.-450G>T
NM_001167618.3:c.-879G>T
NM_001167619.3:c.-792G>T
NM_001258271.2:c.67G>T
NM_001258273.2:c.-566G>T
NM_001258274.3:c.-1029G>T
NM_001354615.2:c.-560G>T
NM_001354616.2:c.-560G>T
NM_001354617.2:c.-652G>T
NM_001354618.2:c.-884G>T
NM_001354619.2:c.-1008G>T
NM_001354620.2:c.-218G>T
NM_001354621.2:c.-977G>T
NM_001354622.2:c.-1090G>T
NM_001354623.2:c.-999G>T
NM_001354624.2:c.-760G>T
NM_001354625.2:c.-658G>T
NM_001354626.2:c.-755G>T
NM_001354627.2:c.-987G>T
NM_001354628.2:c.67G>T
NM_001354629.2:c.67G>T
NM_001354630.2:c.67G>T
NP_000240.1:p.Glu23Ter
NP_000240.1:p.Glu23Ter
NP_001245200.1:p.Glu23Ter
NP_001341557.1:p.Glu23Ter
NP_001341558.1:p.Glu23Ter
NP_001341559.1:p.Glu23Ter
LRG_216t1:c.67G>T
LRG_216:g.5265G>T
LRG_216p1:p.Glu23Ter
NC_000003.11:g.37035105G>T
NM_000249.3:c.67G>T

Protein change:

E23*

Links:

dbSNP: rs63750823

NCBI 1000 Genomes Browser:

rs63750823

Molecular consequence:

NM_001167617.3:c.-450G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-879G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-792G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-566G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-1029G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-560G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-560G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-652G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-884G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-1008G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-218G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-977G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1090G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-999G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-760G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-658G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-755G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-987G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001434923	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004186427	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Jul 10, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001434923

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 1, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004186427

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Jul 10, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434923.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This c.67G>T (p.Glu23*) variant in the MLH1 gene was predicted to result in an early stop codon, however, RT-PCR analysis indicates that the nucleotide change creates a new consensus donor splice site which results in the deletion of the last 51 nucleotides/17 residues of exon 1, rather than an early termination codon (PMID 16736291). Thus, this variant causes a splicing defect rather than early truncation of the protein. The deleted portion of exon 1 comprises an essential portion of the ATPase domain and thus is predicted to be a loss of function mutation, which is known to be a disease-causing mechanism for colorectal cancer. This variant has been reported in multiple unrelated families with colorectal cancer that fulfill Amsterdam I or II criteria, or have diagnoses of Lynch Syndrome (PMID 16736291, 11754112, 15849733 and 24333619). The tumors analyzed from patients with this variant have lost immunohistochemical staining for MLH1 and have been MSI-high. This variant is not been observed in the general population databases. Therefore, the c.67G>T (p.Glu23*) variant in the MLH1 gene is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004186427.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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