NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del) AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Aug 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000202279.30

Allele description [Variation Report for NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del)]

NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del)

Other names:

MLH1, 3-BP DEL, LYS618; K616del

HGVS:

NC_000003.11:g.37089123_37089125del
NC_000003.12:g.37047633AAG[2]
NG_007109.2:g.59284AAG[2]
NM_000249.4:c.1846AAG[2]MANE SELECT
NM_001167617.3:c.1552AAG[2]
NM_001167618.3:c.1123AAG[2]
NM_001167619.3:c.1123AAG[2]
NM_001258271.2:c.1846AAG[2]
NM_001258273.2:c.1123AAG[2]
NM_001258274.3:c.1123AAG[2]
NM_001354615.2:c.1123AAG[2]
NM_001354616.2:c.1123AAG[2]
NM_001354617.2:c.1123AAG[2]
NM_001354618.2:c.1123AAG[2]
NM_001354619.2:c.1123AAG[2]
NM_001354620.2:c.1552AAG[2]
NM_001354621.2:c.823AAG[2]
NM_001354622.2:c.823AAG[2]
NM_001354623.2:c.823AAG[2]
NM_001354624.2:c.772AAG[2]
NM_001354625.2:c.772AAG[2]
NM_001354626.2:c.772AAG[2]
NM_001354627.2:c.772AAG[2]
NM_001354628.2:c.1846AAG[2]
NM_001354629.2:c.1747AAG[2]
NM_001354630.2:c.1732-885GAA[2]
NP_000240.1:p.Lys618del
NP_001161089.1:p.Lys520del
NP_001161090.1:p.Lys377del
NP_001161091.1:p.Lys377del
NP_001245200.1:p.Lys618del
NP_001245202.1:p.Lys377del
NP_001245203.1:p.Lys377del
NP_001341544.1:p.Lys377del
NP_001341545.1:p.Lys377del
NP_001341546.1:p.Lys377del
NP_001341547.1:p.Lys377del
NP_001341548.1:p.Lys377del
NP_001341549.1:p.Lys520del
NP_001341550.1:p.Lys277del
NP_001341551.1:p.Lys277del
NP_001341552.1:p.Lys277del
NP_001341553.1:p.Lys260del
NP_001341554.1:p.Lys260del
NP_001341555.1:p.Lys260del
NP_001341556.1:p.Lys260del
NP_001341557.1:p.Lys618del
NP_001341558.1:p.Lys585del
LRG_216:g.59284AAG[2]
NC_000003.11:g.37089123_37089125del
NC_000003.11:g.37089124AAG[2]
NC_000003.11:g.37089130_37089132del
NC_000003.11:g.37089130_37089132delAAG
NM_000249.3:c.1845_1847delGAA
NM_000249.3:c.1852_1854delAAG
NM_000249.4:c.1845_1847delMANE SELECT
NM_000249.4:c.1852_1854delMANE SELECT
NM_000249.4:c.1852_1854delAAGMANE SELECT
p.K616del
p.K618del

Protein change:

K260del; LYS616DEL

Links:

OMIM: 120436.0003; OMIM: 120436.0018; dbSNP: rs63751247

NCBI 1000 Genomes Browser:

rs63751247

Molecular consequence:

NM_000249.4:c.1846AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167617.3:c.1552AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167618.3:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001167619.3:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258271.2:c.1846AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258273.2:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001258274.3:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354615.2:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354616.2:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354617.2:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354618.2:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354619.2:c.1123AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354620.2:c.1552AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354621.2:c.823AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354622.2:c.823AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354623.2:c.823AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354624.2:c.772AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354625.2:c.772AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354626.2:c.772AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354627.2:c.772AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354628.2:c.1846AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354629.2:c.1747AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354630.2:c.1732-885GAA[2] - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

Unknown function
loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000211081	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 21, 2020)	germline	clinical testing	Citation Link,
SCV000257069	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	research
SCV000885706	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Apr 11, 2018)	germline	clinical testing	Citation Link,
SCV001450056	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001469800	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Dec 28, 2019)	unknown	clinical testing	PubMed (39) [See all records that cite these PMIDs] 9718327, 8993976, 8581513, 10480359, 10422993, 10037723, 8571956, 16083711, 14961575, 17510385, 12810663, 17594722, 21120944, 24362816, 26681312, 28135145, 28449805, 28874130, 30693488, 30720243, 30787465, 31332305, 31350202, 33504652, 34178123, 9697702, 11427529, 16451135, 7661930, 22949379, 12891553, 20591884, 23047549, 25117503, 28176205, 29520894, 29929473, 30521064, 26467025
SCV001744362	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001967790	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002017491	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 29, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002550855	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	5	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls.

Farrington SM, Lin-Goerke J, Ling J, Wang Y, Burczak JD, Robbins DJ, Dunlop MG.

Am J Hum Genet. 1998 Sep;63(3):749-59.

PubMed [citation]

PMID:: 9718327
PMCID:: PMC1377385

Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer.

Viel A, Genuardi M, Capozzi E, Leonardi F, Bellacosa A, Paravatou-Petsotas M, Pomponi MG, Fornasarig M, Percesepe A, Roncucci L, Tamassia MG, Benatti P, Ponz de Leon M, Valenti A, Covino M, Anti M, Foletto M, Boiocchi M, Neri G.

Genes Chromosomes Cancer. 1997 Jan;18(1):8-18.

PubMed [citation]

PMID:: 8993976

See all PubMed Citations (40)

Details of each submission

From GeneDx, SCV000211081.14

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

Description

Published functional studies demonstrate a damaging effect: decreased MLH1 protein expression, reduced MMR activity relative to wildtype, and reduced interaction with PMS2 and EXO1 (Guerrette 1999, Kondo 2003, Takahashi 2007); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27435373, 27247567, 25980754, 28449805, 30376427, 8581513, 9697702, 10037723, 12810663, 16083711, 17510385, 17594722, 20591884, 21120944, 22949379, 24362816, 25117503, 7661930, 18726168, 15996210, 21681552, 25430799, 26777316, 28176205, 23047549, 26681312, 28127413, 28874130, 28640387, 17846840, 28135145, 29520894, 30693488, 12891553, 29929473, 29478780, 10422993, 30402230, 18566915, 29345684, 31350202, 9311737, 31332305, 33504652)

#	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

From Mayo Clinic Laboratories, Mayo Clinic, SCV000257069.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		5	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885706.1

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

Description

The MLH1 c.1852_1854delAAG; p.Lys618del variant (rs63751247), also known as Lys616del, is a common alteration in individuals diagnosed with Lynch syndrome, and segregates with the disorder (Miyaki 1995, Raevaara 2003, LOVD InSiGHT database). Functional characterization of the variant protein indicates reduced mismatch repair activity due to decreased steady state levels of MLH1 protein (Raevaara 2005, Shimodaira 1998, Takehashi 2007) and reduced localization with PMS2 and EXO1 (Kondo 2003, Raevaara 2005). It is classified as pathogenic in ClinVar (Variation ID: 17080) by the International Society for Gastrointestinal Hereditary Tumours (Thompson 2014). Based on available information, this variant is considered pathogenic. REFERENCES LOVD InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php?select_db=MLH1 Kondo E et al. A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res. 2003; 63(12):3302-8. Miyaki M et al. Germ line mutations of hMSH2 and hMLH1 genes in Japanese families with hereditary nonpolyposis colorectal cancer (HNPCC): usefulness of DNA analysis for screening and diagnosis of HNPCC patients. J Mol Med (Berl). 1995; 73(10):515-20. Raevaara T et al. Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein. Gastroenterology. 2003; 125(2):501-9. Raevaara T et al. Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology. 2005; 129(2):537-49. Shimodaira H et al. Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae. Nat Genet. 1998; 19(4):384-9. Takahashi M et al. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007; 67(10):4595-604. Thompson B et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2014; 46(2):107-15.

#	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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450056.1

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

#	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		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469800.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (39)

Description

This variant has been reported in individuals affected with colorectal, endometrial, ovarian, bladder, and prostate cancers and Lynch Syndrome in the published literature (PMIDs: 30521064 (2019), 29929473 (2018), 28176205 (2017), 25117503 (2014), 23047549 (2012), and 20591884 (2010)). In addition, studies indicate that this variant has deleterious effects on MLH1 protein expression in yeast and human cell based functional studies (PMIDs: 29520894 (2018), 16083711 (2005), and 12891553 (2003)). Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001744362.3

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

#	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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001967790.1

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

#	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

From Revvity Omics, Revvity, SCV002017491.3

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

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002550855.4

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

#	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: Apr 20, 2024

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