NM_000249.3(MLH1):c.298C>T (p.Arg100Ter) AND Lynch syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 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:: RCV000030223.3

Allele description

NM_000249.3(MLH1):c.298C>T (p.Arg100Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.3(MLH1):c.298C>T (p.Arg100Ter)

HGVS:

NC_000003.12:g.37001045C>T
NM_000249.3:c.298C>T
NM_001258271.1:c.298C>T
NP_000240.1:p.Arg100Ter
NP_001245200.1:p.Arg100Ter
LRG_216t1:c.298C>T
LRG_216:g.12696C>T
LRG_216p1:p.Arg100Ter
NC_000003.11:g.37042536C>T
p.Arg100*
p.Arg100X

Protein change:

R100*

Links:

dbSNP: rs63751221

NCBI 1000 Genomes Browser:

rs63751221

Molecular consequence:

NM_000249.3:c.298C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Lynch syndrome (HNPCC)
Synonyms:: Hereditary nonpolyposis colon cancer
Identifiers:: MedGen: C1333990; OMIM: PS120435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000052890	Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	pathogenic (Aug 18, 2011)	germline	curation, clinical testing	PubMed (15) [See all records that cite these PMIDs] 15872200, 14512394, 10480359, 18415027, 15235038, 17312306, 10995807, 17453009, 15955785, 15475387, 17267619, 19698169, 19224586, 15849733, 11606497 Citation Link,
SCV000106619	InSiGHT	reviewed by expert panel (Guidelines v1.9)	Pathogenic (Sep 5, 2013)	germline	research	Citation Link,
SCV000543562	Invitae,	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 4, 2016)	germline	clinical testing	Citation Link,
SCV000592344	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 27, 2013)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19698169, 17267619, 15872200, 17312306, 15849733, 10995807, 11606497, 14635101, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	8	not provided	not provided	8	not provided	literature only, clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer.

Renkonen E, Zhang Y, Lohi H, Salovaara R, Abdel-Rahman WM, Nilbert M, Aittomaki K, Jarvinen HJ, Mecklin JP, Lindblom A, Peltomaki P.

J Clin Oncol. 2003 Oct 1;21(19):3629-37.

PubMed [citation]

PMID:: 14512394

Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.

Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A.

Hum Genet. 1999 Jul-Aug;105(1-2):79-85.

PubMed [citation]

PMID:: 10480359

See all PubMed Citations (17)

Details of each submission

From Laboratory Corporation of America, SCV000052890.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	curation	PubMed (15)
2	not provided	5	not provided	not provided	curation	PubMed (15)
3	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

"The variant, listed as a pathogenic mutation, was detected in 3 patients who meet the Bethesda criteria for HNPCC diagnosis; controls not tested.": PubMed [ID: 15849733]
"The variant was detected in a large family who meet the Amsterdam criteria for HNPCC diagnosis; 27 members are affected; 5 were genotyped and showed to carry the variant; controls not tested.": PubMed [ID: 14512394]

Description

Converted during submission to Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	3	not provided	not provided		3	not provided	not provided	not provided
2	germline	yes	5	not provided	not provided		5	not provided	not provided	not provided
3	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 3

Co-occurrences

#	Zygosity	Alleles	Number of Observations
3	SingleHeterozygote	MLH1:c.1668-19A>G, MLH1:c.655A>G	1

From InSiGHT, SCV000106619.2

#	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 Invitae,, SCV000543562.1

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

Description

This sequence change creates a premature translational stop signal at codon 100 (p.Arg100*) of the MLH1 gene. It is expected to result in an absent or disrupted protein product. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in the literature in patients affected with Hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 11606497, 17312306, 15872200). Additionally, this mutation has been shown to co-segregate with disease in HPNCC families (PMID: 10480359, 14512394, 15235038) For these reasons, this variant has been 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 Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592344.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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

Last Updated: Dec 19, 2017

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