NM_000249.4(MLH1):c.208-3C>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 30, 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:: RCV000562969.3

Allele description [Variation Report for NM_000249.4(MLH1):c.208-3C>G]

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 cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000669543	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (May 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15991306, 19267393, 25980754, 26681312 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000669543

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(May 30, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

Gene symbol: MLH1. Disease: Hereditary nonpolyposis colorectal cancer.

Otway R, Tetlow N, Hornby J, Doe WF, Kohonen-Corish MR.

Hum Genet. 2005 May;116(6):535. No abstract available. Erratum in: Hum Genet. 2005 Dec;118(3-4):533.

PubMed [citation]

PMID:: 15991306

Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics.

Arnold S, Buchanan DD, Barker M, Jaskowski L, Walsh MD, Birney G, Woods MO, Hopper JL, Jenkins MA, Brown MA, Tavtigian SV, Goldgar DE, Young JP, Spurdle AB.

Hum Mutat. 2009 May;30(5):757-70. doi: 10.1002/humu.20936.

PubMed [citation]

PMID:: 19267393
PMCID:: PMC2707453

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000669543.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.208-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 3 in the MLH1 gene. This alteration has been reported in multiple individuals with MLH1/PMS2-absent, microsatellite unstable, HNPCC-related tumors (Arnold S, Hum. Mutat. 2009 May; 30(5):757-70; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and analysis of patient-derived RNA found that this alteration results in aberrant splicing leading to transcripts lacking coding exon 3 (Otway R, Hum. Genet. 2005 May; 116(6):535; Arnold S, Hum. Mutat. 2009 May; 30(5):757-70). This alteration also co-segregates with HNPCC-related tumors in multiple families (Arnold S, Hum. Mutat. 2009 May; 30(5):757-70; Ambry internal data). This nucleotide position is poorly conserved in available vertebrate species. In addition, 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.

#	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: Feb 20, 2024

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