NM_000249.4(MLH1):c.208-3C>G AND Hereditary nonpolyposis colorectal neoplasms

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 25, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000524274.7

Allele description

NM_000249.4(MLH1):c.208-3C>G

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.208-3C>G

HGVS:

NC_000003.12:g.37000952C>G
NG_007109.2:g.12603C>G
NM_000249.4:c.208-3C>GMANE SELECT
NM_001167617.3:c.-82-3C>G
NM_001167618.3:c.-516-3C>G
NM_001167619.3:c.-424-3C>G
NM_001258271.2:c.208-3C>G
NM_001258273.2:c.-516-3C>G
NM_001258274.3:c.-516-3C>G
NM_001354615.2:c.-419-3C>G
NM_001354616.2:c.-424-3C>G
NM_001354617.2:c.-516-3C>G
NM_001354618.2:c.-516-3C>G
NM_001354619.2:c.-516-3C>G
NM_001354620.2:c.-82-3C>G
NM_001354621.2:c.-609-3C>G
NM_001354622.2:c.-722-3C>G
NM_001354623.2:c.-722-3C>G
NM_001354624.2:c.-619-3C>G
NM_001354625.2:c.-522-3C>G
NM_001354626.2:c.-619-3C>G
NM_001354627.2:c.-619-3C>G
NM_001354628.2:c.208-3C>G
NM_001354629.2:c.208-3449C>G
NM_001354630.2:c.208-3C>G
LRG_216t1:c.208-3C>G
LRG_216:g.12603C>G
NC_000003.11:g.37042443C>G
NM_000249.3:c.208-3C>G

Links:

dbSNP: rs267607720

NCBI 1000 Genomes Browser:

rs267607720

Molecular consequence:

NM_000249.4:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167617.3:c.-82-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167618.3:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001167619.3:c.-424-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258271.2:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258273.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001258274.3:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354615.2:c.-419-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354616.2:c.-424-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354617.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354618.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354619.2:c.-516-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354620.2:c.-82-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354621.2:c.-609-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354622.2:c.-722-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-722-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354624.2:c.-619-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-522-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-619-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-619-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354628.2:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354629.2:c.208-3449C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354630.2:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000284047	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 25, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17576681, 9536098, 25980754, 15991306, 19267393, 26681312, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000284047

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 25, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000284047.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (Deletion of Exon 3) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 15991306, 19267393, 25980754). ClinVar contains an entry for this variant (Variation ID: 90032). This variant is also known as IVS2-3C>G. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15991306, 19267393, 26681312). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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