NM_000249.4(MLH1):c.453+20G>T AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Mar 2, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000249.4(MLH1):c.453+20G>T]


MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000003.12:g.37007083G>T
  • NG_007109.2:g.18734G>T
  • NM_000249.4:c.453+20G>TMANE SELECT
  • NM_001167617.3:c.159+20G>T
  • NM_001167618.3:c.-271+20G>T
  • NM_001167619.3:c.-179+20G>T
  • NM_001258271.2:c.453+20G>T
  • NM_001258273.2:c.-271+20G>T
  • NM_001258274.3:c.-271+20G>T
  • NM_001354615.2:c.-179+20G>T
  • NM_001354616.2:c.-179+20G>T
  • NM_001354617.2:c.-271+20G>T
  • NM_001354618.2:c.-271+20G>T
  • NM_001354619.2:c.-271+20G>T
  • NM_001354620.2:c.159+20G>T
  • NM_001354621.2:c.-364+20G>T
  • NM_001354622.2:c.-477+20G>T
  • NM_001354623.2:c.-477+20G>T
  • NM_001354624.2:c.-374+20G>T
  • NM_001354625.2:c.-282+20G>T
  • NM_001354626.2:c.-374+20G>T
  • NM_001354627.2:c.-374+20G>T
  • NM_001354628.2:c.453+20G>T
  • NM_001354629.2:c.354+20G>T
  • NM_001354630.2:c.453+20G>T
  • LRG_216t1:c.453+20G>T
  • LRG_216:g.18734G>T
  • NC_000003.11:g.37048574G>T
  • NM_000249.3:c.453+20G>T
dbSNP: rs759417195
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000249.4:c.453+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167617.3:c.159+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167618.3:c.-271+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167619.3:c.-179+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258271.2:c.453+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258273.2:c.-271+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258274.3:c.-271+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354615.2:c.-179+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354616.2:c.-179+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354617.2:c.-271+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354618.2:c.-271+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354619.2:c.-271+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354620.2:c.159+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354621.2:c.-364+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354622.2:c.-477+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-477+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354624.2:c.-374+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-282+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-374+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-374+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354628.2:c.453+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354629.2:c.354+20G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354630.2:c.453+20G>T - intron variant - [Sequence Ontology: SO:0001627]


MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000513615GeneDxcriteria provided, single submitter
Likely benign
(Oct 31, 2017)
germlineclinical testing

Citation Link,

SCV001519514Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Mar 2, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000513615.4

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


This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001519514.1

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


Variant summary: MLH1 c.453+20G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251216 control chromosomes, predominantly at a frequency of 0.00023 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (4e-05 vs 0.00071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.453+20G>T in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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

Last Updated: Nov 27, 2021

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