NM_000249.3(MLH1):c.-7C>T AND not provided

Clinical significance:Uncertain significance (Last evaluated: Jan 12, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:

Allele description


MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000003.12:g.36993541C>T
  • NG_007109.2:g.5192C>T
  • NM_000249.3:c.-7C>T
  • NM_001167617.1:c.-523C>T
  • LRG_216t1:c.-7C>T
  • LRG_216:g.5192C>T
  • NC_000003.10:g.37010036C>T
  • NC_000003.11:g.37035032C>T
dbSNP: rs104894994
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001167617.1:c.-523C>T - 2KB upstream variant - [Sequence Ontology: SO:0001636]
  • NM_000249.3:c.-7C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000148740Harris Lab, University of Minnesotano assertion providednot providedunknownnot provided

SCV000149357GeneDxcriteria provided, single submitter
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownnot providednot providednot providednot provided1not providedliterature only

Details of each submission

From Harris Lab, University of Minnesota, SCV000148740.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot providednot provided
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnot provided1not providednot providednot providednot providednot providednot provided

From GeneDx, SCV000149357.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


This variant is denoted MLH1 c.-7C>T, and describes a nucleotide substitution 7 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is CTGG[C/T]GCCA. According to the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database, MLH1 c.-7C>T is an uncertain variant based on insufficient evidence and has been reported to co-occur with MLH1 c.-28A>G in individuals with a personal and/or family history suggestive of Lynch syndrome, as well as in a hereditary prostate cancer family (Fredriksson 2006, Thompson 2014, Hesson 2015, Lagerstedt-Robinson 2016). In one study of two such individuals from suspected Lynch syndrome families, these variants conferred an approximate 50% reduction in MLH1 expression, although there was no MLH1 promoter methylation and the promoter remained epigenetically unaltered (Hesson 2015). Although this variant does not appear to affect the start codon or the Kozak translational consensus sequence, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome and variants located within the 5?UTR have been shown to result in allele-specific promoter methylation and subsequent transcriptional silencing (Hitchins 2011, Ward 2013). This variant was observed at an allele frequency of 0.88% (56/6,614) in individuals of Finnish ancestry in large population cohorts and the base that is altered is conserved through mammals (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). At this time, we consider MLH1 c.-7C>T to be a variant of uncertain significance.

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

Last Updated: Mar 30, 2019

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