NM_000249.4(MLH1):c.1752_1772del (p.Leu585_Asp591del) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 5, 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:: RCV003029071.3

Allele description [Variation Report for NM_000249.4(MLH1):c.1752_1772del (p.Leu585_Asp591del)]

NM_000249.4(MLH1):c.1752_1772del (p.Leu585_Asp591del)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1752_1772del (p.Leu585_Asp591del)

HGVS:

NC_000003.12:g.37047539_37047559del
NG_007109.2:g.59190_59210del
NM_000249.4:c.1752_1772delMANE SELECT
NM_001167617.3:c.1458_1478del
NM_001167618.3:c.1029_1049del
NM_001167619.3:c.1029_1049del
NM_001258271.2:c.1752_1772del
NM_001258273.2:c.1029_1049del
NM_001258274.3:c.1029_1049del
NM_001354615.2:c.1029_1049del
NM_001354616.2:c.1029_1049del
NM_001354617.2:c.1029_1049del
NM_001354618.2:c.1029_1049del
NM_001354619.2:c.1029_1049del
NM_001354620.2:c.1458_1478del
NM_001354621.2:c.729_749del
NM_001354622.2:c.729_749del
NM_001354623.2:c.729_749del
NM_001354624.2:c.678_698del
NM_001354625.2:c.678_698del
NM_001354626.2:c.678_698del
NM_001354627.2:c.678_698del
NM_001354628.2:c.1752_1772del
NM_001354629.2:c.1653_1673del
NM_001354630.2:c.1732-978_1732-958del
NP_000240.1:p.Leu585_Asp591del
NP_000240.1:p.Leu585_Asp591del
NP_001161089.1:p.Leu487_Asp493del
NP_001161090.1:p.Leu344_Asp350del
NP_001161091.1:p.Leu344_Asp350del
NP_001245200.1:p.Leu585_Asp591del
NP_001245202.1:p.Leu344_Asp350del
NP_001245203.1:p.Leu344_Asp350del
NP_001341544.1:p.Leu344_Asp350del
NP_001341545.1:p.Leu344_Asp350del
NP_001341546.1:p.Leu344_Asp350del
NP_001341547.1:p.Leu344_Asp350del
NP_001341548.1:p.Leu344_Asp350del
NP_001341549.1:p.Leu487_Asp493del
NP_001341550.1:p.Leu244_Asp250del
NP_001341551.1:p.Leu244_Asp250del
NP_001341552.1:p.Leu244_Asp250del
NP_001341553.1:p.Leu227_Asp233del
NP_001341554.1:p.Leu227_Asp233del
NP_001341555.1:p.Leu227_Asp233del
NP_001341556.1:p.Leu227_Asp233del
NP_001341557.1:p.Leu585_Asp591del
NP_001341558.1:p.Leu552_Asp558del
LRG_216t1:c.1752_1772del21
LRG_216:g.59190_59210del
LRG_216p1:p.Leu585_Asp591del
NC_000003.11:g.37089028_37089048del
NC_000003.11:g.37089030_37089050del
NM_000249.3:c.1752_1772del21

Molecular consequence:

NM_000249.4:c.1752_1772del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167617.3:c.1458_1478del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167618.3:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167619.3:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258271.2:c.1752_1772del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258273.2:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258274.3:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354615.2:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354616.2:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354617.2:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354618.2:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354619.2:c.1029_1049del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354620.2:c.1458_1478del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354621.2:c.729_749del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354622.2:c.729_749del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354623.2:c.729_749del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354624.2:c.678_698del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354625.2:c.678_698del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354626.2:c.678_698del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354627.2:c.678_698del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354628.2:c.1752_1772del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354629.2:c.1653_1673del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354630.2:c.1732-978_1732-958del - intron variant - [Sequence Ontology: SO:0001627]

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
SCV003326465	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16395668, 30998989, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003326465

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 5, 2022)

germline

clinical testing

PubMed (3)
[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

Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing.

Auclair J, Busine MP, Navarro C, Ruano E, Montmain G, Desseigne F, Saurin JC, Lasset C, Bonadona V, Giraud S, Puisieux A, Wang Q.

Hum Mutat. 2006 Feb;27(2):145-54.

PubMed [citation]

PMID:: 16395668

Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome.

Bouvet D, Bodo S, Munier A, Guillerm E, Bertrand R, Colas C, Duval A, Coulet F, Muleris M.

Gastroenterology. 2019 Aug;157(2):421-431. doi: 10.1053/j.gastro.2019.03.071. Epub 2019 Apr 15.

PubMed [citation]

PMID:: 30998989

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003326465.2

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

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.Ala586Asp) have been determined to be pathogenic (PMID: 16395668, 30998989; 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. 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 variant, c.1752_1772del, results in the deletion of 7 amino acid(s) of the MLH1 protein (p.Leu585_Asp591del), but otherwise preserves the integrity of the reading frame.

#	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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