NM_000249.4(MLH1):c.67G>T (p.Glu23Ter) AND Hereditary nonpolyposis colon cancer

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 27, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001290676.1

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:: Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:: Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:: MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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PREDICTED: ergosterol biosynthetic protein 28 [Cucumis sativus]
PREDICTED: ergosterol biosynthetic protein 28 [Cucumis sativus]
gi|449436908|ref|XP_004136234.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001478808	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 27, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15849733, 11754112, 26681312, 16736291 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001478808

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 27, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.

Mangold E, Pagenstecher C, Friedl W, Mathiak M, Buettner R, Engel C, Loeffler M, Holinski-Feder E, Müller-Koch Y, Keller G, Schackert HK, Krüger S, Goecke T, Moeslein G, Kloor M, Gebert J, Kunstmann E, Schulmann K, Rüschoff J, Propping P.

Int J Cancer. 2005 Sep 20;116(5):692-702.

PubMed [citation]

PMID:: 15849733

Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis colorectal cancer.

Krüger S, Plaschke J, Pistorius S, Jeske B, Haas S, Krämer H, Hinterseher I, Bier A, Kreuz FR, Theissig F, Saeger HD, Schackert HK.

Hum Mutat. 2002 Jan;19(1):82.

PubMed [citation]

PMID:: 11754112

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478808.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: MLH1 c.67G>T (p.Glu23X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250858 control chromosomes (gnomAD and publication data). c.67G>T has been reported in the literature in individuals affected with colon cancer and HNPCC (Kruger_2001, Mangold_2005, Baehring_2006, Susswein_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. In addition, one expert panel (InSiGHT) classified this variant as pathogenic in 2013. Based on the evidence outlined above, the variant was 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

Last Updated: Sep 29, 2024

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