NM_000249.4(MLH1):c.1852_1853delinsGC (p.Lys618Ala) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jul 7, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000018620.18

Allele description [Variation Report for NM_000249.4(MLH1):c.1852_1853delinsGC (p.Lys618Ala)]

NM_000249.4(MLH1):c.1852_1853delinsGC (p.Lys618Ala)

Gene:

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

Variant type:

Indel

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1852_1853delinsGC (p.Lys618Ala)

HGVS:

NC_000003.12:g.37047639_37047640delinsGC
NG_007109.2:g.59290_59291delinsGC
NM_000249.4:c.1852_1853delinsGCMANE SELECT
NM_001167617.3:c.1558_1559delinsGC
NM_001167618.3:c.1129_1130delinsGC
NM_001167619.3:c.1129_1130delinsGC
NM_001258271.2:c.1852_1853delinsGC
NM_001258273.2:c.1129_1130delinsGC
NM_001258274.3:c.1129_1130delinsGC
NM_001354615.2:c.1129_1130delinsGC
NM_001354616.2:c.1129_1130delinsGC
NM_001354617.2:c.1129_1130delinsGC
NM_001354618.2:c.1129_1130delinsGC
NM_001354619.2:c.1129_1130delinsGC
NM_001354620.2:c.1558_1559delinsGC
NM_001354621.2:c.829_830delinsGC
NM_001354622.2:c.829_830delinsGC
NM_001354623.2:c.829_830delinsGC
NM_001354624.2:c.778_779delinsGC
NM_001354625.2:c.778_779delinsGC
NM_001354626.2:c.778_779delinsGC
NM_001354627.2:c.778_779delinsGC
NM_001354628.2:c.1852_1853delinsGC
NM_001354629.2:c.1753_1754delinsGC
NM_001354630.2:c.1732-878_1732-877delinsGC
NP_000240.1:p.Lys618Ala
NP_001161089.1:p.Lys520Ala
NP_001161090.1:p.Lys377Ala
NP_001161091.1:p.Lys377Ala
NP_001245200.1:p.Lys618Ala
NP_001245202.1:p.Lys377Ala
NP_001245203.1:p.Lys377Ala
NP_001341544.1:p.Lys377Ala
NP_001341545.1:p.Lys377Ala
NP_001341546.1:p.Lys377Ala
NP_001341547.1:p.Lys377Ala
NP_001341548.1:p.Lys377Ala
NP_001341549.1:p.Lys520Ala
NP_001341550.1:p.Lys277Ala
NP_001341551.1:p.Lys277Ala
NP_001341552.1:p.Lys277Ala
NP_001341553.1:p.Lys260Ala
NP_001341554.1:p.Lys260Ala
NP_001341555.1:p.Lys260Ala
NP_001341556.1:p.Lys260Ala
NP_001341557.1:p.Lys618Ala
NP_001341558.1:p.Lys585Ala
LRG_216:g.59290_59291delinsGC
NC_000003.11:g.37089130_37089131delinsGC
NM_000249.3:c.1852_1853delAAinsGC
NM_000249.4:c.1852_1853delinsGC
NM_001354630.1:c.1732-878_1732-877delinsGC
p.K618A

Protein change:

K260A; LYS618ALA

Links:

OMIM: 120436.0012; dbSNP: rs35502531

NCBI 1000 Genomes Browser:

rs35502531

Molecular consequence:

NM_001354630.2:c.1732-878_1732-877delinsGC - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.1852_1853delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1558_1559delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1852_1853delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1129_1130delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1558_1559delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.829_830delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.829_830delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.829_830delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.778_779delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.778_779delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.778_779delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.778_779delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1852_1853delinsGC - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1753_1754delinsGC - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038903	OMIM	no assertion criteria provided	Uncertain significance (Aug 1, 2010)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10598809, 20533529
SCV000781761	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001440472	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004015880	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jul 7, 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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Missense mutations in hMLH1 associated with colorectal cancer.

Liu T, Tannergård P, Hackman P, Rubio C, Kressner U, Lindmark G, Hellgren D, Lambert B, Lindblom A.

Hum Genet. 1999 Nov;105(5):437-41.

PubMed [citation]

PMID:: 10598809

Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.

Kosinski J, Hinrichsen I, Bujnicki JM, Friedhoff P, Plotz G.

Hum Mutat. 2010 Aug;31(8):975-82. doi: 10.1002/humu.21301.

PubMed [citation]

PMID:: 20533529
PMCID:: PMC2908215

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000038903.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, has been reclassified based on the findings of Kosinski et al. (2010).

Liu et al. (1999) described 2 germline missense mutations in exon 16 of the MLH1 gene associated with colorectal cancer (609310): lys618-to-ala (K618A) and glu578-to-gly (E578G; 120436.0013). The tumors did not show the usual DNA microsatellite instability (MSI) and would have been missed if this method was used for selection of patients for mutation screening.

Using in vitro functional expression studies, Kosinski et al. (2010) demonstrated that the K618A variant was fully expressed and retained MMR activity, and that PMS2 (600259) was stable. The authors classified K618A as a variant of uncertain significance rather than as a disease-causing variant.

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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781761.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440472.1

#	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004015880.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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