NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 20, 2022
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:: RCV000129328.13

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_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_216t1:c.1846_1848AAG[2]
LRG_216:g.59284AAG[2]
LRG_216p1:p.Lys618del
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.1846_1848AAG[2]
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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184091	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 20, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10037723, 16451135, 17510385, 18270343, 18566915, 23047549 Citation Link,
SCV000186087	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (9/4/14))	Pathogenic (Jan 22, 2013)	germline	clinical testing	Citation Link,
SCV000684776	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 6, 2021)	germline	clinical testing	PubMed (28) [See all records that cite these PMIDs] 7661930, 8581513, 8993976, 9311737, 9697702, 10037723, 10422993, 10480359, 11427529, 12414824, 12547705, 12810663, 12891553, 14635101, 16083711, 17453009, 17510385, 18373977, 18566915, 19267393, 19419416, 21120944, 25280751, 28176205, 28640387, 29520894, 31491536, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184091

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 20, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000186087

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (9/4/14))

Pathogenic
(Jan 22, 2013)

germline

clinical testing

Citation Link,

SCV000684776

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 6, 2021)

germline

clinical testing

PubMed (28)
[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 MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Kurzawski G, Suchy J, Lener M, Kłujszo-Grabowska E, Kładny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Góźdź S, Niepsuj S, Słomski R, Pławski A, Łacka-Wojciechowska A, Rozmiarek A, et al.

Clin Genet. 2006 Jan;69(1):40-7.

PubMed [citation]

PMID:: 16451135

The frequency of Muir-Torre syndrome among Lynch syndrome families.

South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A.

J Natl Cancer Inst. 2008 Feb 20;100(4):277-81. doi: 10.1093/jnci/djm291. Epub 2008 Feb 12.

PubMed [citation]

PMID:: 18270343

See all PubMed Citations (31)

Details of each submission

From Ambry Genetics, SCV000184091.4

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

Description

The c.1852_1854delAAG pathogenic mutation (also known as p.K618del), located in coding exon 16 of the MLH1 gene, results from an in-frame AAG deletion at nucleotide positions 1852 to 1854 causing the in-frame deletion of a highly conserved lysine at codon 618. In one yeast study, this mutation (designated as 1846-48del) exhibited 38.9% in vitro MMR activity and less than 25% of MLH1 protein expression when compared to wild-type (Takahashi M et al. Cancer Res. 2007 May;67:4595-604). In another study analyzing the dimerization of MLH1 and PMS2 proteins it was noted that the lysine at codon 618, when mutated, led to nearly undetectable interaction levels with PMS2 when compared to wild-type (Guerrette S et al. J. Biol. Chem. 1999 Mar;274:6336-41). This mutation has been reported in multiple families with HNPCC/Lynch syndrome and/or Lynch syndrome associated cancers (Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7; Takahashi M et al. Cancer Res. 2007 May;67:4595-604; South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81; Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623). This alteration has also been detected by our laboratory in multiple individuals diagnosed with an early-onset MLH1-associated cancer whose tumors demonstrated absent MLH1 and PMS2 staining on immunohistochemistry (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 Ambry Genetics, SCV000186087.2

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

From Color Diagnostics, LLC DBA Color Health, SCV000684776.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (28)

Description

This variant is a 1 amino acid deletion located in exon 16 of the MLH1 protein. The variant is also known as del616 in the literature. Multiple experimental functional studies have shown that this variant significantly abrogates MLH1 protein function by reducing MLH1 protein expression or stability, and reducing interaction with PMS2 and EXO1 (PMID: 10037723, 11427529, 12810663, 12891553, 16083711, 17510385, 18373977, 21120944, 29520894, 9697702). This variant has been reported in numerous individuals affected with Lynch Syndrome cancers (PMID: 10422993, 10480359, 12414824, 12547705, 12891553, 12891553, 14635101, 17453009, 18566915, 19267393, 19419416, 25280751, 28176205, 28640387, 29520894, 31491536, 7661930, 8581513, 8993976, 8993976, 9311737). It has also been shown to segregate with disease in Lynch Syndrome families (PMID: 12891553, 8993976). This variant has been identified in 1/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	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: Mar 16, 2025

ClinVar

Relating variation to medicine