VCV000017080.57 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

28 submissions

26 submitters

10 conditions

Reviewed by expert panel

Pathogenic

Sep 2013 by International …

for Lynch Syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 17080 Accession: VCV000017080.57

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 3p22.2 3: 37047632-37047634 (GRCh38) [ NCBI UCSC ] 3: 37089130-37089132 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 7, 2015	Sep 8, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.1845_1847del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		inframe deletion
NM_000249.4:c.1846AAG[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Lys618del	inframe deletion
NM_000249.4:c.1852_1854del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		inframe deletion
NM_000249.4:c.1852_1854delAAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		inframe deletion
NM_000249.3:c.1845_1847delGAA		inframe indel
NM_000249.3:c.1852_1854delAAG		inframe indel
NM_001167617.3:c.1552AAG[2]	NP_001161089.1:p.Lys520del	inframe deletion
NM_001167618.3:c.1123AAG[2]	NP_001161090.1:p.Lys377del	inframe deletion
NM_001167619.3:c.1123AAG[2]	NP_001161091.1:p.Lys377del	inframe deletion
NM_001258271.2:c.1846AAG[2]	NP_001245200.1:p.Lys618del	inframe deletion
NM_001258273.2:c.1123AAG[2]	NP_001245202.1:p.Lys377del	inframe deletion
NM_001258274.3:c.1123AAG[2]	NP_001245203.1:p.Lys377del	inframe deletion
NM_001354615.2:c.1123AAG[2]	NP_001341544.1:p.Lys377del	inframe deletion
NM_001354616.2:c.1123AAG[2]	NP_001341545.1:p.Lys377del	inframe deletion
NM_001354617.2:c.1123AAG[2]	NP_001341546.1:p.Lys377del	inframe deletion
NM_001354618.2:c.1123AAG[2]	NP_001341547.1:p.Lys377del	inframe deletion
NM_001354619.2:c.1123AAG[2]	NP_001341548.1:p.Lys377del	inframe deletion
NM_001354620.2:c.1552AAG[2]	NP_001341549.1:p.Lys520del	inframe deletion
NM_001354621.2:c.823AAG[2]	NP_001341550.1:p.Lys277del	inframe deletion
NM_001354622.2:c.823AAG[2]	NP_001341551.1:p.Lys277del	inframe deletion
NM_001354623.2:c.823AAG[2]	NP_001341552.1:p.Lys277del	inframe deletion
NM_001354624.2:c.772AAG[2]	NP_001341553.1:p.Lys260del	inframe deletion
NM_001354625.2:c.772AAG[2]	NP_001341554.1:p.Lys260del	inframe deletion
NM_001354626.2:c.772AAG[2]	NP_001341555.1:p.Lys260del	inframe deletion
NM_001354627.2:c.772AAG[2]	NP_001341556.1:p.Lys260del	inframe deletion
NM_001354628.2:c.1846AAG[2]	NP_001341557.1:p.Lys618del	inframe deletion
NM_001354629.2:c.1747AAG[2]	NP_001341558.1:p.Lys585del	inframe deletion
NM_001354630.2:c.1732-885GAA[2]		intron variant
NC_000003.12:g.37047633AAG[2]
NC_000003.11:g.37089124AAG[2]
NG_007109.2:g.59284AAG[2]
LRG_216:g.59284AAG[2]
LRG_216t1:c.1846_1848AAG[2]	LRG_216p1:p.Lys618del

... more HGVS ... less HGVS

Protein change

K618del, K377del, K520del, K277del, K585del, K260del

Other names

MLH1, 3-BP DEL, LYS618
K616del

Canonical SPDI

NC_000003.12:37047631:GAAGAAGAAG:GAAGAAG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

Unknown function

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 120436.0018 dbSNP: rs63751247 ClinGen: CA007087 OMIM: 120436.0003 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MLH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	5693	5754

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mismatch repair cancer syndrome 1	Pathogenic (1)	no assertion criteria provided	Dec 11, 2017	RCV000018609.30
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 20, 2022	RCV000129328.13
Lynch syndrome	Pathogenic (3)	reviewed by expert panel	Sep 5, 2013	RCV000075383.12
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 16, 2024	RCV000192399.15
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000202279.30
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 20, 2024	RCV000524254.11
Lynch syndrome 1	Pathogenic (2)	criteria provided, single submitter	-	RCV001093699.5
Carcinoma of colon	Pathogenic (1)	no assertion criteria provided	-	RCV001353903.4
Lynch-like syndrome	Pathogenic (1)	no assertion criteria provided	Jul 1, 2019	RCV001249999.3
Colorectal cancer, hereditary nonpolyposis, type 2 Mismatch repair cancer syndrome 1 Muir-Torré syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 22, 2022	RCV002490387.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 05, 2013)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch Syndrome Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000106376.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comment: Abrogated function (reduced expression in 2 independent assays), >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Pathogenic (Jan 22, 2013)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (9/4/14)) Method: clinical testing	Neoplastic Syndromes, Hereditary Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186087.2 First in ClinVar: Aug 06, 2014 Last updated: Mar 24, 2015
Pathogenic (Apr 11, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885706.1 First in ClinVar: Jul 24, 2016 Last updated: Jul 24, 2016	Comment: 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 … (more) 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. (less)
Pathogenic (Dec 26, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917668.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (11) PubMed: 18373977‚ 29520894‚ 16083711‚ 10037723‚ 9718327‚ 24362816‚ 10480359‚ 17510385‚ 22949379‚ 8993976‚ 28640387 Comment: Variant summary: MLH1 c.1852_1854delAAG (p.Lys618del) results in an in-frame deletion that is predicted to remove one Lys amino acid from the C-terminal domain (IPR032189) of … (more) Variant summary: MLH1 c.1852_1854delAAG (p.Lys618del) results in an in-frame deletion that is predicted to remove one Lys amino acid from the C-terminal domain (IPR032189) of the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 246244 control chromosomes (gnomAD). c.1852_1854delAAG has been reported in the literature in multiple individuals affected with Lynch Syndrome (e.g. Viel 1997, Wang 1999, Farrington 1998, Raevaara 2005, Ricker 2017, Koger 2018). In many of these cases the tumor tissue was shown to be MLH1/PMS2 negative by IHC, and microsatellite instable (e.g. Ricker 2017, Koger 2018). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, demonstrating reduced expression and MMR activity (e.g. Takahashi 2007, Koger 2018). Multi-factorial likelihood analysis also suggested a pathogenic role for the variant (Thompson 2013, Thompson 2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450056.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 21, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000211081.14 First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019	Comment: 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 … (more) 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) (less)
Pathogenic (Nov 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002102409.1 First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022	Comment: A heterozygous 3 base pair deletion in exon 16 of the MLH1 gene (Depth: 275x) that results in the in-frame deletion of amino acid, Lysine … (more) A heterozygous 3 base pair deletion in exon 16 of the MLH1 gene (Depth: 275x) that results in the in-frame deletion of amino acid, Lysine at codon 618 (p.Lys618del) was detected. This in-frame deletion reduces the functional activity of the MLH1 protein and is documented as pathogenic in hereditary nonpolyposis colon cancer in the ClinVar database. The p.Lys618del variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is damaging by MutationTaster2 tool. The reference region is conserved across species. (less) Clinical Features: Hereditary nonpolyposis colorectal carcinoma (present) , Mucinous colorectal carcinoma (present) Age: 20-29 years Sex: male Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) Accession: SCV002573624.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Publications: PubMed (1) PubMed: 36073783 Age: 50-59 years Sex: male Geographic origin: Algeria
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muir-Torré syndrome Mismatch repair cancer syndrome 1 Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002780667.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002550855.4 First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023
Pathogenic (Feb 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193023.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Jan 20, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000255268.12 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (9) PubMed: 28492532‚ 10422993‚ 12891553‚ 22949379‚ 10037723‚ 11427529‚ 12810663‚ 17510385‚ 21120944 Comment: This variant, c.1852_1854del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Lys618del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.1852_1854del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Lys618del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782285, gnomAD 0.0009%). This variant has been observed in individual(s) with Lynch syndrome (PMID: 10422993, 12891553). It has also been observed to segregate with disease in related individuals. This variant is also known as del616. ClinVar contains an entry for this variant (Variation ID: 17080). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). Experimental studies have shown that this variant affects MLH1 function (PMID: 10037723, 11427529, 12810663, 12891553, 17510385, 21120944). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 20, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000184091.4 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 10037723‚ 16451135‚ 17510385‚ 18270343‚ 18566915‚ 23047549 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 05, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000248052.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Apr 20, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488529.2 First in ClinVar: Jan 02, 2016 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 17510385‚ 17453009‚ 12891553‚ 24362816‚ 22949379
Pathogenic (Dec 28, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001469800.2 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024	Publications: PubMed (38) PubMed: 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 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017491.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000684776.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (27) PubMed: 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 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004843223.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (27) PubMed: 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 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Aug 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: yes Allele origin: germline	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili Accession: SCV005200620.1 First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024	Number of individuals with the variant: 1 Age: 40-49 years Sex: female Ethnicity/Population group: Latin Geographic origin: Colombia
Pathogenic (-)	no assertion criteria provided Method: research	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257069.1 First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015	Number of individuals with the variant: 5
Pathogenic (Dec 11, 2017)	no assertion criteria provided Method: literature only	MISMATCH REPAIR CANCER SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038892.3 First in ClinVar: Apr 04, 2013 Last updated: Feb 07, 2015	Publications: Hamilton, S. R., Liu, B., Parsons, (more...) Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. The molecular basis of Turcot's syndrome. New Eng. J. Med. 332: 839-847, 1995. Comment on evidence: In a man with mismatch repair cancer syndrome (MMRCS; 276300), Hamilton et al. (1995) identified a 3-bp deletion (AAG) in the MLH1 gene, resulting in … (more) In a man with mismatch repair cancer syndrome (MMRCS; 276300), Hamilton et al. (1995) identified a 3-bp deletion (AAG) in the MLH1 gene, resulting in the loss of a lysine at codon 618. The patient had adenocarcinomas of the ascending and transverse colon at the age of 30, adenomas of the descending and sigmoid colon at the ages of 32 and 33, and an ileal adenocarcinoma and a glioblastoma multiforme at the age of 33. There was a family history of HNPCC. The patient was also reported to have a transitional cell carcinoma of the ureter. (less)
Pathogenic (Jul 01, 2019)	no assertion criteria provided Method: clinical testing	Lynch-like syndrome Affected status: yes Allele origin: somatic	Constitutional Genetics Lab, Leon Berard Cancer Center Accession: SCV001423900.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Carcinoma of colon Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000592424.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021	Comment: The p.Lys618del variant was identified in 14 of 3448 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome (Nilbert 2009, Overbeek 2007, Raevaara … (more) The p.Lys618del variant was identified in 14 of 3448 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome (Nilbert 2009, Overbeek 2007, Raevaara 2005). The variant was also identified in dbSNP (ID: rs121912962) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, HGMD, UMD (117X as a causal variant), â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, and the COSMIC database, and the ClinVar database where it was classified as a pathogenic variant by two submitters (OMIM and InSiGHT). This variant is an in-frame deletion resulting in the removal of a lysine (Lys) residue at codon 618, within the 3-lysine region including codons 616â€šÃ„Ã¬618. Shimodaira (1998) notes that this variant co-segregates with disease, and tumours with the variant have shown high microsatellite instability and loss of MLH1 by immunohistochemistry staining (Raevaara 2005, Overbeek 2007). Functional assays have demonstrated a deleterious effect of the variant, including reduced MLH1 expression, reduced protein interactions with ExoI and/or PMS2, abnormal nuclear localization, reduced mismatch repair activity, and loss or reduction of the dominant mutator effect as compared to wild type MLH1 (Raevaara 2005, Schmutte 2001 Shimodaira 1998, Takahashi 2007). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less) Number of individuals with the variant: 6
Pathogenic (Apr 01, 2009)	no assertion criteria provided Method: literature only	LYNCH SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038910.5 First in ClinVar: Apr 04, 2013 Last updated: Jun 02, 2024	Publications: PubMed (3) PubMed: 14635101‚ 8581513‚ 19419416 Comment on evidence: In 4 cases of hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Taylor et al. (2003) found deletion of 3 nucleotides, 1846_1848delAAG, resulting in deletion of lys616 … (more) In 4 cases of hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Taylor et al. (2003) found deletion of 3 nucleotides, 1846_1848delAAG, resulting in deletion of lys616 (K616del) from the MLH1 protein. This mutation had previously been observed by Miyaki et al. (1995). Taylor et al. (2003) used the multiplex ligation-dependent probe amplification (MLDA) assay to demonstrate the deletion. Tang et al. (2009) identified a heterozygous 1846_1848delAAG mutation in affected members of 5 Taiwanese families with HNPCC2. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Lynch syndrome 1 Affected status: yes Allele origin: germline	Ding PR Lab, Sun Yat-sen University Cancer Center Accession: SCV001250883.1 First in ClinVar: May 19, 2020 Last updated: May 19, 2020	Age: 40-49 years Sex: male Geographic origin: China
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744362.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967790.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Citation text

Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. The molecular basis of Turcot's syndrome. New Eng. J. Med. 332: 839-847, 1995.

Comment:

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.

Comment:

Variant summary: MLH1 c.1852_1854delAAG (p.Lys618del) results in an in-frame deletion that is predicted to remove one Lys amino acid from the C-terminal domain (IPR032189) of the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 246244 control chromosomes (gnomAD). c.1852_1854delAAG has been reported in the literature in multiple individuals affected with Lynch Syndrome (e.g. Viel 1997, Wang 1999, Farrington 1998, Raevaara 2005, Ricker 2017, Koger 2018). In many of these cases the tumor tissue was shown to be MLH1/PMS2 negative by IHC, and microsatellite instable (e.g. Ricker 2017, Koger 2018). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, demonstrating reduced expression and MMR activity (e.g. Takahashi 2007, Koger 2018). Multi-factorial likelihood analysis also suggested a pathogenic role for the variant (Thompson 2013, Thompson 2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

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)

Comment:

A heterozygous 3 base pair deletion in exon 16 of the MLH1 gene (Depth: 275x) that results in the in-frame deletion of amino acid, Lysine at codon 618 (p.Lys618del) was detected. This in-frame deletion reduces the functional activity of the MLH1 protein and is documented as pathogenic in hereditary nonpolyposis colon cancer in the ClinVar database. The p.Lys618del variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is damaging by MutationTaster2 tool. The reference region is conserved across species.

Comment:

This variant, c.1852_1854del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Lys618del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782285, gnomAD 0.0009%). This variant has been observed in individual(s) with Lynch syndrome (PMID: 10422993, 12891553). It has also been observed to segregate with disease in related individuals. This variant is also known as del616. ClinVar contains an entry for this variant (Variation ID: 17080). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). Experimental studies have shown that this variant affects MLH1 function (PMID: 10037723, 11427529, 12810663, 12891553, 17510385, 21120944). For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The p.Lys618del variant was identified in 14 of 3448 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome (Nilbert 2009, Overbeek 2007, Raevaara 2005). The variant was also identified in dbSNP (ID: rs121912962) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, HGMD, UMD (117X as a causal variant), â€šÃ„ÃºMismatch Repair Genes Variant Databaseâ€šÃ„Ã¹, â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, and the COSMIC database, and the ClinVar database where it was classified as a pathogenic variant by two submitters (OMIM and InSiGHT). This variant is an in-frame deletion resulting in the removal of a lysine (Lys) residue at codon 618, within the 3-lysine region including codons 616â€šÃ„Ã¬618. Shimodaira (1998) notes that this variant co-segregates with disease, and tumours with the variant have shown high microsatellite instability and loss of MLH1 by immunohistochemistry staining (Raevaara 2005, Overbeek 2007). Functional assays have demonstrated a deleterious effect of the variant, including reduced MLH1 expression, reduced protein interactions with ExoI and/or PMS2, abnormal nuclear localization, reduced mismatch repair activity, and loss or reduction of the dominant mutator effect as compared to wild type MLH1 (Raevaara 2005, Schmutte 2001 Shimodaira 1998, Takahashi 2007). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Unknown function	DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.	Result not provided	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002102409.1
loss_of_function_variant (SO:0002054)			University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) Accession: SCV002573624.1	Publications PubMed (1)

Citation text

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study.	Boumehdi AL	Annals of human genetics	2022	PMID: 36073783
Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study.	Yang M	Therapeutic advances in medical oncology	2021	PMID: 34178123
Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies.	Tlemsani C	Science translational medicine	2021	PMID: 33504652
The spectrum of Lynch syndrome-associated germ-line mutations in Russia.	Yanus GA	European journal of medical genetics	2020	PMID: 31491536
Next Generation Sequencing Reveals Novel Mutations in Mismatch Repair Genes and Other Cancer Predisposition Genes in Asian Patients with Suspected Lynch Syndrome.	Ow SGW	Clinical colorectal cancer	2019	PMID: 31350202
Full-length transcript amplification and sequencing as universal method to test mRNA integrity and biallelic expression in mismatch repair genes.	Morak M	European journal of human genetics : EJHG	2019	PMID: 31332305
Toward automation of germline variant curation in clinical cancer genetics.	Ravichandran V	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30787465
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.	Soussi T	Human mutation	2019	PMID: 30720243
Lynch-like syndrome is as frequent as Lynch syndrome in early-onset nonfamilial nonpolyposis colorectal cancer.	Antelo M	International journal of cancer	2019	PMID: 30693488
Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.	Jiang W	International journal of cancer	2019	PMID: 30521064
A Chinese family affected by lynch syndrome caused by MLH1 mutation.	Jia S	BMC medical genetics	2018	PMID: 29929473
Evaluation of MLH1 variants of unclear significance.	Köger N	Genes, chromosomes & cancer	2018	PMID: 29520894
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.	Rossi BM	BMC cancer	2017	PMID: 28874130
DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer.	Ricker CN	Cancer	2017	PMID: 28640387
Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome.	Sunga AY	Cancer genetics	2017	PMID: 28449805
Correlation between germline mutations in MMR genes and microsatellite instability in ovarian cancer specimens.	Akbari MR	Familial cancer	2017	PMID: 28176205
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.	Yurgelun MB	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28135145
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC).	Newton K	Journal of medical genetics	2014	PMID: 25280751
High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry.	Rosty C	Familial cancer	2014	PMID: 25117503
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.	Thompson BA	Nature genetics	2014	PMID: 24362816
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.	Thompson BA	Human mutation	2013	PMID: 22949379
Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.	Pal T	British journal of cancer	2012	PMID: 23047549
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants.	Kansikas M	Human mutation	2011	PMID: 21120944
Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers.	van der Post RS	Journal of medical genetics	2010	PMID: 20591884
Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene.	Tang R	Clinical genetics	2009	PMID: 19419416
Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics.	Arnold S	Human mutation	2009	PMID: 19267393
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.	Nilbert M	Familial cancer	2009	PMID: 18566915
The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations.	Zhao N	Biochemical and biophysical research communications	2008	PMID: 18373977
The frequency of Muir-Torre syndrome among Lynch syndrome families.	South CD	Journal of the National Cancer Institute	2008	PMID: 18270343
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes.	Ou J	Human mutation	2007	PMID: 17594722
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.	Takahashi M	Cancer research	2007	PMID: 17510385
Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer.	Overbeek LI	British journal of cancer	2007	PMID: 17453009
Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).	Kurzawski G	Clinical genetics	2006	PMID: 16451135
Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.	Raevaara TE	Gastroenterology	2005	PMID: 16083711
Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden.	Cederquist K	International journal of cancer	2004	PMID: 14961575
Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA.	Taylor CF	Human mutation	2003	PMID: 14635101
Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein.	Raevaara TE	Gastroenterology	2003	PMID: 12891553
A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.	Kondo E	Cancer research	2003	PMID: 12810663
Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors.	Hendriks Y	The American journal of pathology	2003	PMID: 12547705
Genetic testing in hereditary non-polyposis colorectal cancer families with a MSH2, MLH1, or MSH6 mutation.	Wagner A	Journal of medical genetics	2002	PMID: 12414824
The interaction of DNA mismatch repair proteins with human exonuclease I.	Schmutte C	The Journal of biological chemistry	2001	PMID: 11427529
Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.	Wang Q	Human genetics	1999	PMID: 10480359
Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing.	Syngal S	JAMA	1999	PMID: 10422993
The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer.	Guerrette S	The Journal of biological chemistry	1999	PMID: 10037723
Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls.	Farrington SM	American journal of human genetics	1998	PMID: 9718327
Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae.	Shimodaira H	Nature genetics	1998	PMID: 9697702
Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations.	Wijnen J	American journal of human genetics	1997	PMID: 9311737
Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer.	Viel A	Genes, chromosomes & cancer	1997	PMID: 8993976
Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16.	Wijnen J	American journal of human genetics	1996	PMID: 8571956
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.	Miyaki M	Journal of molecular medicine (Berlin, Germany)	1995	PMID: 8581513
The molecular basis of Turcot's syndrome.	Hamilton SR	The New England journal of medicine	1995	PMID: 7661930
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.1852_1854del	-	-	-	-
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Text-mined citations for rs63751247 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63751247 ...