VCV000405416.4 - ClinVar

NM_000249.4(MLH1):c.2136del (p.Ser711_Trp712insTer)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000249.4(MLH1):c.2136del (p.Ser711_Trp712insTer)

Variation ID: 405416 Accession: VCV000405416.4

Type and length

Deletion, 1 bp

Location

Cytogenetic: 3p22.2 3: 37050517 (GRCh38) [ NCBI UCSC ] 3: 37092008 (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	Apr 17, 2017	Feb 28, 2024	Jul 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000249.4:c.2136del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000240.1:p.Ser711_Trp712insTer	nonsense
NM_000249.3:c.2136delG
NM_001167617.3:c.1842del	NP_001161089.1:p.Ser613_Trp614insTer	nonsense
NM_001167618.3:c.1413del	NP_001161090.1:p.Ser470_Trp471insTer	nonsense
NM_001167619.3:c.1413del	NP_001161091.1:p.Ser470_Trp471insTer	nonsense
NM_001258271.2:c.1929del	NP_001245200.1:p.Ser642_Trp643insTer	nonsense
NM_001258273.2:c.1413del	NP_001245202.1:p.Ser470_Trp471insTer	nonsense
NM_001258274.3:c.1413del	NP_001245203.1:p.Ser470_Trp471insTer	nonsense
NM_001354615.2:c.1413del	NP_001341544.1:p.Ser470_Trp471insTer	nonsense
NM_001354616.2:c.1413del	NP_001341545.1:p.Ser470_Trp471insTer	nonsense
NM_001354617.2:c.1413del	NP_001341546.1:p.Ser470_Trp471insTer	nonsense
NM_001354618.2:c.1413del	NP_001341547.1:p.Ser470_Trp471insTer	nonsense
NM_001354619.2:c.1413del	NP_001341548.1:p.Ser470_Trp471insTer	nonsense
NM_001354620.2:c.1842del	NP_001341549.1:p.Ser613_Trp614insTer	nonsense
NM_001354621.2:c.1113del	NP_001341550.1:p.Ser370_Trp371insTer	nonsense
NM_001354622.2:c.1113del	NP_001341551.1:p.Ser370_Trp371insTer	nonsense
NM_001354623.2:c.1113del	NP_001341552.1:p.Ser370_Trp371insTer	nonsense
NM_001354624.2:c.1062del	NP_001341553.1:p.Ser353_Trp354insTer	nonsense
NM_001354625.2:c.1062del	NP_001341554.1:p.Ser353_Trp354insTer	nonsense
NM_001354626.2:c.1062del	NP_001341555.1:p.Ser353_Trp354insTer	nonsense
NM_001354627.2:c.1062del	NP_001341556.1:p.Ser353_Trp354insTer	nonsense
NM_001354628.2:c.2043del	NP_001341557.1:p.Ser680_Trp681insTer	nonsense
NM_001354629.2:c.2037del	NP_001341558.1:p.Ser678_Trp679insTer	nonsense
NM_001354630.2:c.1971del	NP_001341559.1:p.Ser656_Trp657insTer	nonsense
NC_000003.12:g.37050518del
NC_000003.11:g.37092009del
NG_007109.2:g.62169del
LRG_216:g.62169del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:37050516:GG:G

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: CA16611269 dbSNP: rs1060500706 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	5691	5752

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.
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Oct 24, 2016	RCV003153591.10
Colorectal cancer, hereditary nonpolyposis, type 2	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2023	RCV003449124.1

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 (Oct 24, 2016)	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: SCV000543613.4 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 8574961‚ 15855432‚ 12624141‚ 12810663‚ 10422993‚ 16338176‚ 20533529 Comment: For these reasons, this variant has been classified as Pathogenic. Different variants (c.2135G>A, 2136G>A) giving rise to the same protein effect observed here (p.Trp712) has … (more) For these reasons, this variant has been classified as Pathogenic. Different variants (c.2135G>A, 2136G>A) giving rise to the same protein effect observed here (p.Trp712) has been reported in individuals affected with Lynch syndrome (PMID: 8574961, 15855432, 12624141). This variant was also shown to be unable to interact with PMS2 in an experimental study (PMID: 12810663). A different truncation downstream of this variant (p.Tyr750) has been determined to be pathogenic (PMID: 10422993, 16338176, 20533529). This suggests that deletion of the C-terminal region of the MLH1 protein is causative of disease. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH1-related disease. This sequence change deletes 1 nucleotide from exon 19 of the MLH1 mRNA (c.2136delG). This creates a premature translational stop signal in the last exon of the MLH1 mRNA (p.Trp712). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 44 amino acids of the MLH1 protein. (less)
Pathogenic (Jul 25, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Colorectal cancer, hereditary nonpolyposis, type 2 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004189968.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

Comment:

For these reasons, this variant has been classified as Pathogenic. Different variants (c.2135G>A, 2136G>A) giving rise to the same protein effect observed here (p.Trp712*) has been reported in individuals affected with Lynch syndrome (PMID: 8574961, 15855432, 12624141). This variant was also shown to be unable to interact with PMS2 in an experimental study (PMID: 12810663). A different truncation downstream of this variant (p.Tyr750*) has been determined to be pathogenic (PMID: 10422993, 16338176, 20533529). This suggests that deletion of the C-terminal region of the MLH1 protein is causative of disease. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH1-related disease. This sequence change deletes 1 nucleotide from exon 19 of the MLH1 mRNA (c.2136delG). This creates a premature translational stop signal in the last exon of the MLH1 mRNA (p.Trp712*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 44 amino acids of the MLH1 protein.

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
Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.	Kosinski J	Human mutation	2010	PMID: 20533529
Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair.	Mohd AB	DNA repair	2006	PMID: 16338176
Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer.	Piñol V	JAMA	2005	PMID: 15855432
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
Cancer risk in 348 French MSH2 or MLH1 gene carriers.	Parc Y	Journal of medical genetics	2003	PMID: 12624141
Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing.	Syngal S	JAMA	1999	PMID: 10422993
Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients.	Liu B	Nature medicine	1996	PMID: 8574961

Text-mined citations for rs1060500706 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000249.4(MLH1):c.2136del (p.Ser711_Trp712insTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1060500706 ...