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

Clinical significance:Pathogenic (Last evaluated: Dec 19, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

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


MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • 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
dbSNP: rs267607720
NCBI 1000 Genomes Browser:
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]


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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000669543Ambry Geneticscriteria provided, single submitter
(Dec 19, 2018)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



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]

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]
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000669543.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)


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). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish 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 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. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Nov 27, 2021

Support Center