NM_000249.4(MLH1):c.184C>T (p.Gln62Ter) AND Lynch syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 5, 2013
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000075379.7

Allele description [Variation Report for NM_000249.4(MLH1):c.184C>T (p.Gln62Ter)]

NM_000249.4(MLH1):c.184C>T (p.Gln62Ter)

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.184C>T (p.Gln62Ter)

HGVS:

NC_000003.12:g.36996686C>T
NG_007109.2:g.8337C>T
NG_008418.1:g.1619G>A
NM_000249.4:c.184C>TMANE SELECT
NM_001167617.3:c.-106C>T
NM_001167618.3:c.-540C>T
NM_001167619.3:c.-448C>T
NM_001258271.2:c.184C>T
NM_001258273.2:c.-517+3023C>T
NM_001258274.3:c.-685C>T
NM_001354615.2:c.-443C>T
NM_001354616.2:c.-448C>T
NM_001354617.2:c.-540C>T
NM_001354618.2:c.-540C>T
NM_001354619.2:c.-540C>T
NM_001354620.2:c.-106C>T
NM_001354621.2:c.-633C>T
NM_001354622.2:c.-746C>T
NM_001354623.2:c.-723+2796C>T
NM_001354624.2:c.-643C>T
NM_001354625.2:c.-546C>T
NM_001354626.2:c.-643C>T
NM_001354627.2:c.-643C>T
NM_001354628.2:c.184C>T
NM_001354629.2:c.184C>T
NM_001354630.2:c.184C>T
NP_000240.1:p.Gln62Ter
NP_000240.1:p.Gln62Ter
NP_001245200.1:p.Gln62Ter
NP_001341557.1:p.Gln62Ter
NP_001341558.1:p.Gln62Ter
NP_001341559.1:p.Gln62Ter
LRG_216t1:c.184C>T
LRG_216:g.8337C>T
LRG_216p1:p.Gln62Ter
NC_000003.11:g.37038177C>T
NM_000249.3:c.184C>T
p.Gln62*

Protein change:

Q62*

Links:

dbSNP: rs63751428

NCBI 1000 Genomes Browser:

rs63751428

Molecular consequence:

NM_001167617.3:c.-106C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-448C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-685C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-443C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-448C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-540C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-106C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-633C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-746C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-643C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-546C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-643C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-643C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3023C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2796C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.184C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106374	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000592333	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 29, 2013)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16451135, 12362047, 7704024, 16034045, 9298827, 25741868
SCV000919646	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 31, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20587412, 10323887 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106374

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v1.9)

Pathogenic
(Sep 5, 2013)

germline

research

Citation Link,

SCV000592333

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 29, 2013)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000919646

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 31, 2018)

germline

clinical testing

PubMed (2)
[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	yes	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, research

Citations

PubMed

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Kurzawski G, Suchy J, Lener M, Kłujszo-Grabowska E, Kładny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, Rozmiarek A, et al.

Clin Genet. 2006 Jan;69(1):40-7.

PubMed [citation]

PMID:: 16451135

Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States.

Kurzawski G, Suchy J, Kładny J, Safranow K, Jakubowska A, Elsakov P, Kucinskas V, Gardovski J, Irmejs A, Sibul H, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Clark J, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, et al.

J Med Genet. 2002 Oct;39(10):E65. No abstract available.

PubMed [citation]

PMID:: 12362047
PMCID:: PMC1734972

See all PubMed Citations (8)

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106374.3

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

Description

Coding sequence variation resulting in a stop codon

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919646.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: MLH1 c.184C>T (p.Gln62X) 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. The variant was absent in 246206 control chromosomes (in gnomAD). c.184C>T has been reported in the literature in multiple individuals from several families meeting Amsterdam Criteria for Lynch Syndrome (Lamberti 1999, Sjursen 2010). These data indicate that the variant is very likely to be associated with disease. In one of these studies it was experimentally confirmed that the variant of interest causes protein truncation (Lamberti 1999), moreover tumor IHC from several samples indicated missing MLH1/PMS2 protein (Sjursen 2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. 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: Oct 20, 2024

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