NM_000249.4(MLH1):c.1758dup (p.Met587fs) AND Hereditary nonpolyposis colon cancer

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 25, 2023
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:: RCV003230396.1

Allele description [Variation Report for NM_000249.4(MLH1):c.1758dup (p.Met587fs)]

NM_000249.4(MLH1):c.1758dup (p.Met587fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1758dup (p.Met587fs)

HGVS:

NC_000003.12:g.37047545dup
NG_007109.2:g.59196dup
NM_000249.4:c.1758dupMANE SELECT
NM_001167617.3:c.1464dup
NM_001167618.3:c.1035dup
NM_001167619.3:c.1035dup
NM_001258271.2:c.1758dup
NM_001258273.2:c.1035dup
NM_001258274.3:c.1035dup
NM_001354615.2:c.1035dup
NM_001354616.2:c.1035dup
NM_001354617.2:c.1035dup
NM_001354618.2:c.1035dup
NM_001354619.2:c.1035dup
NM_001354620.2:c.1464dup
NM_001354621.2:c.735dup
NM_001354622.2:c.735dup
NM_001354623.2:c.735dup
NM_001354624.2:c.684dup
NM_001354625.2:c.684dup
NM_001354626.2:c.684dup
NM_001354627.2:c.684dup
NM_001354628.2:c.1758dup
NM_001354629.2:c.1659dup
NM_001354630.2:c.1732-972dup
NP_000240.1:p.Met587fs
NP_001161089.1:p.Met489fs
NP_001161090.1:p.Met346fs
NP_001161091.1:p.Met346fs
NP_001245200.1:p.Met587fs
NP_001245202.1:p.Met346fs
NP_001245203.1:p.Met346fs
NP_001341544.1:p.Met346fs
NP_001341545.1:p.Met346fs
NP_001341546.1:p.Met346fs
NP_001341547.1:p.Met346fs
NP_001341548.1:p.Met346fs
NP_001341549.1:p.Met489fs
NP_001341550.1:p.Met246fs
NP_001341551.1:p.Met246fs
NP_001341552.1:p.Met246fs
NP_001341553.1:p.Met229fs
NP_001341554.1:p.Met229fs
NP_001341555.1:p.Met229fs
NP_001341556.1:p.Met229fs
NP_001341557.1:p.Met587fs
NP_001341558.1:p.Met554fs
LRG_216:g.59196dup
NC_000003.11:g.37089034_37089035insC
NC_000003.11:g.37089036dup
NM_000249.3:c.1758dupC

Protein change:

M229fs

Links:

dbSNP: rs63749863

NCBI 1000 Genomes Browser:

rs63749863

Molecular consequence:

NM_000249.4:c.1758dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1464dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.1758dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1035dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1464dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.735dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.735dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.735dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.684dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.1758dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.1659dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.1732-972dup - intron variant - [Sequence Ontology: SO:0001627]

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

Recent activity

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PREDICTED: Homo sapiens Fc receptor like 2 (FCRL2), transcript variant X2, mRNA
PREDICTED: Homo sapiens Fc receptor like 2 (FCRL2), transcript variant X2, mRNA
gi|2462513513|ref|XM_054338695.1|

Nucleotide
PREDICTED: Homo sapiens Fc receptor like 2 (FCRL2), transcript variant X7, mRNA
PREDICTED: Homo sapiens Fc receptor like 2 (FCRL2), transcript variant X7, mRNA
gi|2462513523|ref|XM_054338700.1|

Nucleotide
SRP117950 (16)
SRA
Mus musculus strain C57BL/6J chromosome 16, GRCm39
Mus musculus strain C57BL/6J chromosome 16, GRCm39
gi|1877089953|gnl|ASM:GCF_000000055 ef|NC_000082.7||gpp|GPC_000007828.1||gnl|NCBI_GENOMES|84

Nucleotide
oocyte maturation factor, partial [Anepischetosia maccoyi]
oocyte maturation factor, partial [Anepischetosia maccoyi]
gi|386779501|gb|AFJ24233.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003928875	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 25, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12810663, 19360343 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003928875

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 25, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

Kondo E, Suzuki H, Horii A, Fukushige S.

Cancer Res. 2003 Jun 15;63(12):3302-8.

PubMed [citation]

PMID:: 12810663

A novel germline mutation of hMLH1 in a Korean hereditary non-polyposis colorectal cancer family.

Kim KH, Kim JY, Oh SI, Baik HW, Kang DW, Jung SH, Rho JH, Hwang IT.

Int J Oncol. 2009 May;34(5):1313-8.

PubMed [citation]

PMID:: 19360343

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928875.1

#	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.1758dupC (p.Met587HisfsX6) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251270 control chromosomes (gnomAD). c.1758dupC has been reported in the literature in individuals affected with Lynch Syndrome, and was shown to segregate with disease in an affected family (e.g. Kim_2009). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating that while the N-terminal portion of the MLH1 protein was detectable, the C-terminal portion was undetectable in patient derived colon tissue samples (Kim_2009), in addition the truncated protein was unable to bind to Pms2 in a yeast two-hybrid assay (Kondo_2003). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 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: Sep 29, 2024

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