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NM_000249.4(MLH1):c.1897-2A>G

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Interpretation:
Likely pathogenic​

Review status:
reviewed by expert panel
Submissions:
8 (Most recent: Sep 25, 2021)
Last evaluated:
Jun 21, 2019
Accession:
VCV000089932.11
Variation ID:
89932
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.1897-2A>G

Allele ID
95406
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 37048515 (GRCh38) GRCh38 UCSC
3: 37090006 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_000249.3:c.1897-2A>G splice acceptor
LRG_216t1:c.1897-2A>G
LRG_216:g.60166A>G
... more HGVS
Protein change
-
Other names
-
Canonical SPDI
NC_000003.12:37048514:A:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Links
ClinGen: CA007469
dbSNP: rs267607871
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 2 reviewed by expert panel Jun 21, 2019 RCV000075411.3
Likely pathogenic 1 criteria provided, single submitter Mar 29, 2021 RCV000487325.2
Likely pathogenic 1 criteria provided, single submitter Jul 7, 2020 RCV000524638.4
Likely pathogenic 1 criteria provided, single submitter Sep 29, 2017 RCV000662785.1
Likely pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000763104.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations May 15, 2020 RCV000570210.4
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MLH1 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3503 3539

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Jun 21, 2019)
reviewed by expert panel
Method: curation
Lynch syndrome
Allele origin: germline
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106407.3
Submitted: (Jun 21, 2019)
Evidence details
Other databases
http://www.insight-database.org/…
Comment:
Interrupts canonical donor splice site
Likely pathogenic
(May 24, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colon cancer
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696134.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (1)
Comment:
Variant summary: The MLH1 c.1897-2A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. … (more)
Likely pathogenic
(Sep 29, 2017)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome II
Allele origin: unknown
Counsyl
Accession: SCV000785594.2
Submitted: (Jun 20, 2018)
Evidence details
Publications
PubMed (3)
Likely pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Muir-Torré syndrome
Turcot syndrome
Lynch syndrome II
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893646.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Likely pathogenic
(May 15, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000908649.2
Submitted: (May 19, 2020)
Comment:
This variant causes an A to G nucleotide substitution at the -2 position of intron 16 of the MLH1 gene. Splice site prediction tools suggest … (more)
Evidence details
Uncertain significance
(Nov 14, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000669547.4
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (3)
Comment:
The c.1897-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 17 in the MLH1 gene. This alteration has … (more)
Likely pathogenic
(Jul 07, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000625106.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (7)
Comment:
This sequence change affects an acceptor splice site in intron 16 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results … (more)
Likely pathogenic
(Mar 29, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000565163.2
Submitted: (Sep 25, 2021)
Evidence details
Comment:
Canonical splice site variant predicted to result in an in-frame deletion of the critical regions of interaction with EXO1, PMS2/MLH3/PMS1 (Plotz 2003, Kosinski 2010, Andersen … (more)

Functional evidence

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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.

Citations for this variant

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Title Author Journal Year Link
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
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
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
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. Pearlman R JAMA oncology 2017 PMID: 27978560
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
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
Splicing in action: assessing disease causing sequence changes. Baralle D Journal of medical genetics 2005 PMID: 16199547
Mutation analysis of hMSH2 and hMLH1 in colorectal cancer patients in India. Rajkumar T Genetic testing 2004 PMID: 15345113
[Heredodegenerative diseases of the nervous system in Africa (apropos of 10 cases)]. Collomb H Bulletin de la Societe medicale d'Afrique noire de langue francaise 1968 PMID: 5713769
http://www.insight-database.org/classifications/?gene=MLH1&variant=c.1897-2A%3EG - - - -

Text-mined citations for rs267607871...

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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 Oct 30, 2021