Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000249.4(MLH1):c.589-2A>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA352042278

619558 (ClinVar)

Gene: MLH1

Condition: Lynch syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: bd985124-a267-45f8-8cc2-bbcbbe4af360

Approved on: 2024-09-19

Published on: 2024-10-11

HGVS expressions

NM_000249.4:c.589-2A>C

NM_000249.4(MLH1):c.589-2A>C

NC_000003.12:g.37012009A>C

CM000665.2:g.37012009A>C

NC_000003.11:g.37053500A>C

CM000665.1:g.37053500A>C

NC_000003.10:g.37028504A>C

NG_007109.2:g.23660A>C

ENST00000413740.2:c.589-2A>C

ENST00000429117.6:c.295-2A>C

ENST00000450420.6:c.589-2A>C

ENST00000456676.7:c.589-2A>C

ENST00000458009.6:c.589-2A>C

ENST00000492474.6:c.-135-2A>C

ENST00000616768.6:c.589-2A>C

ENST00000673673.2:c.589-2A>C

ENST00000231790.8:c.589-2A>C

ENST00000413212.2:c.-135-2A>C

ENST00000432299.6:c.*669-2A>C

ENST00000441265.6:c.-135-2A>C

ENST00000442249.6:n.604-2A>C

ENST00000447829.6:c.226-2A>C

ENST00000539477.6:c.-135-2A>C

ENST00000673673.1:c.542-2A>C

ENST00000673713.1:n.620-2A>C

ENST00000673715.1:c.589-2A>C

ENST00000673897.1:c.*381-2A>C

ENST00000673899.1:c.589-2A>C

ENST00000673947.1:c.*729-2A>C

ENST00000673972.1:c.*467-2A>C

ENST00000673990.1:n.574-2A>C

ENST00000674019.1:c.-135-2A>C

ENST00000674107.1:n.531-2A>C

ENST00000674111.1:c.589-2A>C

ENST00000231790.6:c.589-2A>C

ENST00000432299.5:c.*669-2A>C

ENST00000435176.5:c.295-2A>C

ENST00000441265.5:c.-135-2A>C

ENST00000442249.5:c.*381-2A>C

ENST00000455445.6:c.-135-2A>C

ENST00000456676.6:c.564-2A>C

ENST00000457004.5:c.*368-2A>C

ENST00000458205.6:c.-135-2A>C

ENST00000536378.5:c.-135-2A>C

ENST00000539477.5:c.-135-2A>C

NM_000249.3:c.589-2A>C

NM_001167617.1:c.295-2A>C

NM_001167618.1:c.-135-2A>C

NM_001167619.1:c.-135-2A>C

NM_001258271.1:c.589-2A>C

NM_001258273.1:c.-135-2A>C

NM_001258274.1:c.-135-2A>C

NM_001167617.2:c.295-2A>C

NM_001167618.2:c.-135-2A>C

NM_001167619.2:c.-135-2A>C

NM_001258274.2:c.-135-2A>C

NM_001354615.1:c.-135-2A>C

NM_001354616.1:c.-135-2A>C

NM_001354617.1:c.-135-2A>C

NM_001354618.1:c.-135-2A>C

NM_001354619.1:c.-135-2A>C

NM_001354620.1:c.295-2A>C

NM_001354621.1:c.-228-2A>C

NM_001354622.1:c.-341-2A>C

NM_001354623.1:c.-341-2A>C

NM_001354624.1:c.-238-2A>C

NM_001354625.1:c.-238-2A>C

NM_001354626.1:c.-238-2A>C

NM_001354627.1:c.-238-2A>C

NM_001354628.1:c.589-2A>C

NM_001354629.1:c.490-2A>C

NM_001354630.1:c.589-2A>C

NM_001167617.3:c.295-2A>C

NM_001167618.3:c.-135-2A>C

NM_001167619.3:c.-135-2A>C

NM_001258271.2:c.589-2A>C

NM_001258273.2:c.-135-2A>C

NM_001258274.3:c.-135-2A>C

NM_001354615.2:c.-135-2A>C

NM_001354616.2:c.-135-2A>C

NM_001354617.2:c.-135-2A>C

NM_001354618.2:c.-135-2A>C

NM_001354619.2:c.-135-2A>C

NM_001354620.2:c.295-2A>C

NM_001354621.2:c.-228-2A>C

NM_001354622.2:c.-341-2A>C

NM_001354623.2:c.-341-2A>C

NM_001354624.2:c.-238-2A>C

NM_001354625.2:c.-238-2A>C

NM_001354626.2:c.-238-2A>C

NM_001354627.2:c.-238-2A>C

NM_001354628.2:c.589-2A>C

NM_001354629.2:c.490-2A>C

NM_001354630.2:c.589-2A>C

Pathogenic

PM2_Supporting PVS1 PP4

Evidence Links 0

Expert Panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Criteria Specification Information

Criteria Specification: ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

The (M_000249.4):c.589-2A>C variant in MLH1 occurs within the canonical splice acceptor site (-2) of intron 7. It is predicted to alter the consensus acceptor splice site leading to exon skipping or use of a cryptic splice site disrupting reading frame and predicting to undergo NMD (PVS1). This variant has been detected in at least one CRC MSI-H tumour with loss of MLH1 and PMS2 expression (PP4). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PVS1, PM2_Sup, PP4 (VCEP specifications version 1).

PM2_Supporting

Absent in gnomAD v2.1, v3.1 and v4.1

PVS1

The variant in NM_000249.4(MLH1):c.589-2A>C affects an acceptor splice site in intron 7 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product and loss-of-function variants in MLH1 are known to be pathogenic (PVS1)

PP4

1 CRC/Endometrial MSI-H tumour using a standard panel of 5-10 markers and/or loss of MMR protein expression consistent with the variant location

Curation History

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