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

Clinical significance:Likely pathogenic (Last evaluated: Jun 21, 2019)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [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_000249.3:c.208-3C>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
dbSNP: rs267607720
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000249.3:c.208-3C>G - intron variant - [Sequence Ontology: SO:0001627]
  • 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]


Lynch syndrome
Familial nonpolyposis colon cancer
MONDO: MONDO:0005835; MedGen: C4552100; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000106518International Society for Gastrointestinal Hereditary Tumours (InSiGHT)reviewed by expert panel
Likely pathogenic
(Jun 21, 2019)

Citation Link,

SCV000887397University of Washington Department of Laboratory Medicine, University of Washingtoncriteria provided, single submitter
Likely pathogenic
(May 1, 2018)
somaticclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedsomaticyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedcuration



Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.

Shirts BH, Konnick EQ, Upham S, Walsh T, Ranola JMO, Jacobson AL, King MC, Pearlman R, Hampel H, Pritchard CC.

Am J Hum Genet. 2018 Jul 5;103(1):19-29. doi: 10.1016/j.ajhg.2018.05.001. Epub 2018 Jun 7.

PubMed [citation]

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106518.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided


Variant causes splicing aberration (not quantified) & 3 MSI-H tumours. Multifactorial likelihood analysis posterior probability 0.95-0.99.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000887397.1

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


MLH1 NM_000249.3:c.208-3C>G has a 97.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1somaticyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 30, 2021

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