NM_000249.4(MLH1):c.2221del (p.Leu741fs) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 9, 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:: RCV003759717.2

Allele description [Variation Report for NM_000249.4(MLH1):c.2221del (p.Leu741fs)]

NM_000249.4(MLH1):c.2221del (p.Leu741fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.2221del (p.Leu741fs)

HGVS:

NC_000003.12:g.37050603del
NG_007109.2:g.62254del
NM_000249.4:c.2221delMANE SELECT
NM_001167617.3:c.1927del
NM_001167618.3:c.1498del
NM_001167619.3:c.1498del
NM_001258271.2:c.2014del
NM_001258273.2:c.1498del
NM_001258274.3:c.1498del
NM_001354615.2:c.1498del
NM_001354616.2:c.1498del
NM_001354617.2:c.1498del
NM_001354618.2:c.1498del
NM_001354619.2:c.1498del
NM_001354620.2:c.1927del
NM_001354621.2:c.1198del
NM_001354622.2:c.1198del
NM_001354623.2:c.1198del
NM_001354624.2:c.1147del
NM_001354625.2:c.1147del
NM_001354626.2:c.1147del
NM_001354627.2:c.1147del
NM_001354628.2:c.2128del
NM_001354629.2:c.2122del
NM_001354630.2:c.2056del
NP_000240.1:p.Leu741Cysfs
NP_000240.1:p.Leu741fs
NP_001161089.1:p.Leu643fs
NP_001161090.1:p.Leu500fs
NP_001161091.1:p.Leu500fs
NP_001245200.1:p.Leu672fs
NP_001245202.1:p.Leu500fs
NP_001245203.1:p.Leu500fs
NP_001341544.1:p.Leu500fs
NP_001341545.1:p.Leu500fs
NP_001341546.1:p.Leu500fs
NP_001341547.1:p.Leu500fs
NP_001341548.1:p.Leu500fs
NP_001341549.1:p.Leu643fs
NP_001341550.1:p.Leu400fs
NP_001341551.1:p.Leu400fs
NP_001341552.1:p.Leu400fs
NP_001341553.1:p.Leu383fs
NP_001341554.1:p.Leu383fs
NP_001341555.1:p.Leu383fs
NP_001341556.1:p.Leu383fs
NP_001341557.1:p.Leu710fs
NP_001341558.1:p.Leu708fs
NP_001341559.1:p.Leu686fs
LRG_216t1:c.2221del
LRG_216:g.62254del
LRG_216p1:p.Leu741Cysfs
NC_000003.11:g.37092093del
NC_000003.11:g.37092094del
NM_000249.3:c.2221delC

Protein change:

L383fs

Molecular consequence:

NM_000249.4:c.2221del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167617.3:c.1927del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167618.3:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167619.3:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258271.2:c.2014del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258273.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001258274.3:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354615.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354616.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354617.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354618.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354619.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354620.2:c.1927del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354621.2:c.1198del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354622.2:c.1198del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354623.2:c.1198del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354624.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354625.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354626.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354627.2:c.1147del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354628.2:c.2128del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354629.2:c.2122del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354630.2:c.2056del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004390081	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8797773, 18566915, 18931482, 24802709, 27295708, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004390081

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 9, 2022)

germline

clinical testing

PubMed (6)
[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

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.

Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H.

Fam Cancer. 2009;8(1):75-83. doi: 10.1007/s10689-008-9199-3. Epub 2008 Jun 20.

PubMed [citation]

PMID:: 18566915

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004390081.1

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

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.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). 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: 1787935). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the MLH1 gene (p.Leu741Cysfs*42). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MLH1 protein and extend the protein by 25 additional amino acid residues.

#	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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