NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 17, 2022
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:: RCV000558933.5

Allele description [Variation Report for NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter)]

NM_000249.4(MLH1):c.2194A>T (p.Lys732Ter)

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.2194A>T (p.Lys732Ter)

HGVS:

NC_000003.12:g.37050576A>T
NG_007109.2:g.62227A>T
NM_000249.4:c.2194A>TMANE SELECT
NM_001167617.3:c.1900A>T
NM_001167618.3:c.1471A>T
NM_001167619.3:c.1471A>T
NM_001258271.2:c.1987A>T
NM_001258273.2:c.1471A>T
NM_001258274.3:c.1471A>T
NM_001354615.2:c.1471A>T
NM_001354616.2:c.1471A>T
NM_001354617.2:c.1471A>T
NM_001354618.2:c.1471A>T
NM_001354619.2:c.1471A>T
NM_001354620.2:c.1900A>T
NM_001354621.2:c.1171A>T
NM_001354622.2:c.1171A>T
NM_001354623.2:c.1171A>T
NM_001354624.2:c.1120A>T
NM_001354625.2:c.1120A>T
NM_001354626.2:c.1120A>T
NM_001354627.2:c.1120A>T
NM_001354628.2:c.2101A>T
NM_001354629.2:c.2095A>T
NM_001354630.2:c.2029A>T
NP_000240.1:p.Lys732Ter
NP_000240.1:p.Lys732Ter
NP_001161089.1:p.Lys634Ter
NP_001161090.1:p.Lys491Ter
NP_001161091.1:p.Lys491Ter
NP_001245200.1:p.Lys663Ter
NP_001245202.1:p.Lys491Ter
NP_001245203.1:p.Lys491Ter
NP_001341544.1:p.Lys491Ter
NP_001341545.1:p.Lys491Ter
NP_001341546.1:p.Lys491Ter
NP_001341547.1:p.Lys491Ter
NP_001341548.1:p.Lys491Ter
NP_001341549.1:p.Lys634Ter
NP_001341550.1:p.Lys391Ter
NP_001341551.1:p.Lys391Ter
NP_001341552.1:p.Lys391Ter
NP_001341553.1:p.Lys374Ter
NP_001341554.1:p.Lys374Ter
NP_001341555.1:p.Lys374Ter
NP_001341556.1:p.Lys374Ter
NP_001341557.1:p.Lys701Ter
NP_001341558.1:p.Lys699Ter
NP_001341559.1:p.Lys677Ter
LRG_216t1:c.2194A>T
LRG_216:g.62227A>T
LRG_216p1:p.Lys732Ter
NC_000003.11:g.37092067A>T
NM_000249.3:c.2194A>T
p.Lys732*

Protein change:

K374*

Links:

dbSNP: rs267607906

NCBI 1000 Genomes Browser:

rs267607906

Molecular consequence:

NM_000249.4:c.2194A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001167617.3:c.1900A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001167618.3:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001167619.3:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258271.2:c.1987A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258273.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001258274.3:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354615.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354616.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354617.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354618.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354619.2:c.1471A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354620.2:c.1900A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354621.2:c.1171A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354622.2:c.1171A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354623.2:c.1171A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354624.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354625.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354626.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354627.2:c.1120A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354628.2:c.2101A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354629.2:c.2095A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354630.2:c.2029A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000625133	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 8797773, 12799449, 16338176, 18566915, 20533529, 24802709, 27295708, 10923051, 25197397, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625133

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

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

Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer.

Han HJ, Yuan Y, Ku JL, Oh JH, Won YJ, Kang KJ, Kim KY, Kim S, Kim CY, Kim JP, Oh NG, Lee KH, Choe KJ, Nakamura Y, Park JG.

J Natl Cancer Inst. 1996 Sep 18;88(18):1317-9. No abstract available.

PubMed [citation]

PMID:: 8797773

N-terminus of hMLH1 confers interaction of hMutLalpha and hMutLbeta with hMutSalpha.

Plotz G, Raedle J, Brieger A, Trojan J, Zeuzem S.

Nucleic Acids Res. 2003 Jun 15;31(12):3217-26.

PubMed [citation]

PMID:: 12799449
PMCID:: PMC162253

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625133.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 12799449, 16338176, 18566915, 20533529, 24802709, 27295708; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90087). This premature translational stop signal has been observed in individual(s) with Muir-Torre syndrome and Lynch syndrome (PMID: 10923051, 25197397). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys732*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the MLH1 protein.

#	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

ClinVar

Relating variation to medicine