VCV000090067.25 - ClinVar

NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del)

Germline

Top reviewed classifications are shown here.

Submission summary:

8 submissions

8 submitters

6 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.210AGA[1] (p.Glu71del)

Variation ID: 90067 Accession: VCV000090067.25

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 3p22.2 3: 37000956-37000958 (GRCh38) [ NCBI UCSC ] 3: 37042447-37042449 (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	Mar 24, 2015	Jul 7, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.210AGA[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Glu71del	inframe deletion
NM_000249.4:c.213_215del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000249.3:c.213_215delAGA
NM_001167617.3:c.-80AGA[1]		5 prime UTR
NM_001167618.3:c.-514AGA[1]		5 prime UTR
NM_001167619.3:c.-422AGA[1]		5 prime UTR
NM_001258271.2:c.210AGA[1]	NP_001245200.1:p.Glu71del	inframe deletion
NM_001258273.2:c.-514AGA[1]		5 prime UTR
NM_001258274.3:c.-514AGA[1]		5 prime UTR
NM_001354615.2:c.-417AGA[1]		5 prime UTR
NM_001354616.2:c.-422AGA[1]		5 prime UTR
NM_001354617.2:c.-514AGA[1]		5 prime UTR
NM_001354618.2:c.-514AGA[1]		5 prime UTR
NM_001354619.2:c.-514AGA[1]		5 prime UTR
NM_001354620.2:c.-80AGA[1]		5 prime UTR
NM_001354621.2:c.-607AGA[1]		5 prime UTR
NM_001354622.2:c.-720AGA[1]		5 prime UTR
NM_001354623.2:c.-720AGA[1]		5 prime UTR
NM_001354624.2:c.-617AGA[1]		5 prime UTR
NM_001354625.2:c.-520AGA[1]		5 prime UTR
NM_001354626.2:c.-617AGA[1]		5 prime UTR
NM_001354627.2:c.-617AGA[1]		5 prime UTR
NM_001354628.2:c.210AGA[1]	NP_001341557.1:p.Glu71del	inframe deletion
NM_001354629.2:c.208-3441_208-3439del		intron variant
NM_001354630.2:c.210AGA[1]	NP_001341559.1:p.Glu71del	inframe deletion
NC_000003.12:g.37000957AGA[1]
NC_000003.11:g.37042448AGA[1]
NG_007109.2:g.12608AGA[1]
LRG_216:g.12608AGA[1]
LRG_216t1:c.213_215del

... more HGVS ... less HGVS

Protein change

E71del

Other names

Canonical SPDI

NC_000003.12:37000955:AAGAAGA:AAGA

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

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

ClinGen: CA008814 LOVD 3: MLH1_000141 OMIM: 120436.0023 dbSNP: rs63751642 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	5694	5755

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.
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic (2)	criteria provided, single submitter	Aug 20, 2023	RCV000018633.26
Lynch syndrome	Pathogenic (1)	reviewed by expert panel	Sep 5, 2013	RCV000075552.4
not provided	Pathogenic (2)	criteria provided, single submitter	Jan 14, 2022	RCV000202299.9
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2021	RCV000565355.4
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jun 27, 2023	RCV000698898.7
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 12, 2021	RCV004584345.1

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: SCV000106545.3 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: Variant allele causes in-frame splicing aberration interrupting ATPase domain: full inactivation of variant allele
Pathogenic (Jan 14, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001759734.3 First in ClinVar: Jul 24, 2021 Last updated: Mar 04, 2023	Comment: In-frame deletion of one amino acid in a non-repeat region; Observed in several individuals with personal or family history consistent with Lynch syndrome (Overbeek 2007, … (more) In-frame deletion of one amino acid in a non-repeat region; Observed in several individuals with personal or family history consistent with Lynch syndrome (Overbeek 2007, Chong 2009, Shigeyasu 2014, Yang 2021); Published functional studies demonstrate a damaging effect: decreased MLH1 protein expression and interaction with PMS2 as well as defective mismatch repair activity in vitro (Raevaara 2002, Raevaara 2005); RT-PCR and mRNA-based assays have found this variant causes skipping of exon 3 due to disruption of an exonic splice enhancer (McVety 2006, Shigeyasu 2014); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.209_211delAAG or c.211_213delGAA; This variant is associated with the following publications: (PMID: 17453009, 19459153, 27829276, 23896635, 21120944, 18561205, 17594722, 16216036, 25504677, 24362816, 22753075, 34178123, 12362032, 16083711, 15923275) (less)
Pathogenic (Aug 20, 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: SCV004190642.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Jun 27, 2023)	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: SCV000827588.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 28492532‚ 15923275‚ 18561205‚ 23896635‚ 12362032‚ 16083711‚ 16216036‚ 17453009‚ 19459153 Comment: This variant, c.213_215del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Glu71del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.213_215del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Glu71del), but otherwise preserves the integrity of the reading frame. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 15923275, 18561205, 23896635). Experimental studies have shown that this variant affects MLH1 function (PMID: 12362032, 16083711). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90067). This variant is also known as 71del and c.209_211delAAG in the literature. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12362032, 16216036, 17453009, 19459153, 23896635). It has also been observed to segregate with disease in related individuals. (less)
Pathogenic (Dec 20, 2021)	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: SCV000669512.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (11) PubMed: 12362032‚ 15923275‚ 16083711‚ 16216036‚ 17453009‚ 17594722‚ 18561205‚ 19459153‚ 21120944‚ 23896635‚ 24362816 Comment: The c.213_215delAGA pathogenic mutation (also known as p.E71del) is located in coding exon 3 of the MLH1 gene. This pathogenic mutation results from an in-frame … (more) The c.213_215delAGA pathogenic mutation (also known as p.E71del) is located in coding exon 3 of the MLH1 gene. This pathogenic mutation results from an in-frame AGA deletion of three nucleotides between nucleotide positions 213 and 215, resulting in the in frame deletion of one amino acid (glutamate) at codon 71. This mutation has been reported in numerous individuals with Lynch syndrome (Chong G et al, Hum. Mutat. 2009 Aug; 30(8):E797-812; Kansikas M et al, Hum. Mutat. 2011 Jan; 32(1):107-15; McVety S et al, J. Med. Genet. 2006 Feb; 43(2):153-6; Mangold E et al, J. Pathol. 2005 Dec; 207(4):385-95; Overbeek LI et al, Br. J. Cancer 2007 May; 96(10):1605-12; Raevaara TE et al, Gastroenterology 2005 Aug; 129(2):537-49). cDNA sequencing indicated that this alteration causes exon 3 skipping during mRNA splicing, suggesting the presence of an exon splicing enhancer (ESE) at the 5' end of exon 3, and inclusion of exon 3 in the mRNA is ESE dependent (McVety S et al. J Med Genet. 2006 Feb;43(2):153-6). Further, multiple functional analyses of this mutation have shown significantly reduced DNA repair efficiency compared to wild type (Raevaara et al. J Med Genet. 2002 Oct;39(10):747-50; Raevaara et al. Gastroenterology. 2005 Aug;129(2):537-49; Ou et al. Hum Mutat. 2007 Nov;28(11):1047-54; Kansikas et al. Hum Mutat. 2011 Jan;32(1):107-15). Of note, this alteration is also designated as c.209_211delAAG and c.211_213delGAA in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Dec 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002578078.2 First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PS3,PM1,PM2,PM4,PP4,PP5 Number of individuals with the variant: 1 Clinical Features: Neoplasm of the large intestine (present) Age: 30-39 years Sex: male Tissue: blood
Pathogenic (-)	no assertion criteria provided Method: research	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257086.1 First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015	Number of individuals with the variant: 1
Pathogenic (Feb 01, 2006)	no assertion criteria provided Method: literature only	LYNCH SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038916.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022	Publications: PubMed (1) PubMed: 15923275 Comment on evidence: McVety et al. (2006) demonstrated the presence of an exon splicing enhancer (ESE) in exon 3 of MLH1 and showed that a 3-bp in-frame deletion … (more) McVety et al. (2006) demonstrated the presence of an exon splicing enhancer (ESE) in exon 3 of MLH1 and showed that a 3-bp in-frame deletion (213_215delAGA) in this ESE was the cause of hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) in a Quebec family. The deletion resulted in loss of codon 71 and caused skipping of exon 3 during mRNA splicing. (less)

Comment:

In-frame deletion of one amino acid in a non-repeat region; Observed in several individuals with personal or family history consistent with Lynch syndrome (Overbeek 2007, Chong 2009, Shigeyasu 2014, Yang 2021); Published functional studies demonstrate a damaging effect: decreased MLH1 protein expression and interaction with PMS2 as well as defective mismatch repair activity in vitro (Raevaara 2002, Raevaara 2005); RT-PCR and mRNA-based assays have found this variant causes skipping of exon 3 due to disruption of an exonic splice enhancer (McVety 2006, Shigeyasu 2014); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.209_211delAAG or c.211_213delGAA; This variant is associated with the following publications: (PMID: 17453009, 19459153, 27829276, 23896635, 21120944, 18561205, 17594722, 16216036, 25504677, 24362816, 22753075, 34178123, 12362032, 16083711, 15923275)

Comment:

This variant, c.213_215del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Glu71del), but otherwise preserves the integrity of the reading frame. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 15923275, 18561205, 23896635). Experimental studies have shown that this variant affects MLH1 function (PMID: 12362032, 16083711). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90067). This variant is also known as 71del and c.209_211delAAG in the literature. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12362032, 16216036, 17453009, 19459153, 23896635). It has also been observed to segregate with disease in related individuals.

Comment:

The c.213_215delAGA pathogenic mutation (also known as p.E71del) is located in coding exon 3 of the MLH1 gene. This pathogenic mutation results from an in-frame AGA deletion of three nucleotides between nucleotide positions 213 and 215, resulting in the in frame deletion of one amino acid (glutamate) at codon 71. This mutation has been reported in numerous individuals with Lynch syndrome (Chong G et al, Hum. Mutat. 2009 Aug; 30(8):E797-812; Kansikas M et al, Hum. Mutat. 2011 Jan; 32(1):107-15; McVety S et al, J. Med. Genet. 2006 Feb; 43(2):153-6; Mangold E et al, J. Pathol. 2005 Dec; 207(4):385-95; Overbeek LI et al, Br. J. Cancer 2007 May; 96(10):1605-12; Raevaara TE et al, Gastroenterology 2005 Aug; 129(2):537-49). cDNA sequencing indicated that this alteration causes exon 3 skipping during mRNA splicing, suggesting the presence of an exon splicing enhancer (ESE) at the 5' end of exon 3, and inclusion of exon 3 in the mRNA is ESE dependent (McVety S et al. J Med Genet. 2006 Feb;43(2):153-6). Further, multiple functional analyses of this mutation have shown significantly reduced DNA repair efficiency compared to wild type (Raevaara et al. J Med Genet. 2002 Oct;39(10):747-50; Raevaara et al. Gastroenterology. 2005 Aug;129(2):537-49; Ou et al. Hum Mutat. 2007 Nov;28(11):1047-54; Kansikas et al. Hum Mutat. 2011 Jan;32(1):107-15). Of note, this alteration is also designated as c.209_211delAAG and c.211_213delGAA in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case.	Shigeyasu K	Surgery today	2014	PMID: 23896635
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants.	Kansikas M	Human mutation	2011	PMID: 21120944
High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families.	Chong G	Human mutation	2009	PMID: 19459153
A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects.	Tournier I	Human mutation	2008	PMID: 18561205
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes.	Ou J	Human mutation	2007	PMID: 17594722
Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer.	Overbeek LI	British journal of cancer	2007	PMID: 17453009
Disruption of an exon splicing enhancer in exon 3 of MLH1 is the cause of HNPCC in a Quebec family.	McVety S	Journal of medical genetics	2006	PMID: 15923275
Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining.	Mangold E	The Journal of pathology	2005	PMID: 16216036
Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.	Raevaara TE	Gastroenterology	2005	PMID: 16083711
Description and functional analysis of a novel in frame mutation linked to hereditary non-polyposis colorectal cancer.	Raevaara TE	Journal of medical genetics	2002	PMID: 12362032
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.213_215del	-	-	-	-
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Text-mined citations for rs63751642 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63751642 ...