NM_000249.3(MLH1):c.404_407delTGAA (p.Leu135Glnfs) AND Lynch syndrome

Clinical significance:Pathogenic (Last evaluated: Sep 5, 2013)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000075702.2

Allele description [Variation Report for NM_000249.3(MLH1):c.404_407delTGAA (p.Leu135Glnfs)]

NM_000249.3(MLH1):c.404_407delTGAA (p.Leu135Glnfs)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.3(MLH1):c.404_407delTGAA (p.Leu135Glnfs)
HGVS:
  • NC_000003.12:g.37007014_37007017delTGAA
  • NG_007109.2:g.18665_18668delTGAA
  • NM_000249.3:c.404_407delTGAA
  • NM_001167618.1:c.-320_-317delTGAA
  • NP_000240.1:p.Leu135Glnfs
  • LRG_216t1:c.404_407delTGAA
  • LRG_216:g.18665_18668delTGAA
  • LRG_216p1:p.Leu135Glnfs
  • NC_000003.11:g.37048505_37048508delTGAA
  • NM_000249.3:c.404_407del
Links:
dbSNP: rs587779014
NCBI 1000 Genomes Browser:
rs587779014
Molecular consequence:
  • NM_001167618.1:c.-320_-317delTGAA - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.3:c.404_407delTGAA - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Lynch syndrome (HNPCC)
Synonyms:
Hereditary nonpolyposis colon cancer
Identifiers:
MedGen: C1333990; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000106705International Society for Gastrointestinal Hereditary Tumours (InSiGHT)reviewed by expert panel
Pathogenic
(Sep 5, 2013)
germlineresearch

Citation Link,

SCV000543531Invitaecriteria provided, single submitter
Pathogenic
(Dec 15, 2016)
germlineclinical testing

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

Description

SCV000106705

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106705.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided

Description

Coding sequence variation resulting in a stop codon

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

From Invitae, SCV000543531.2

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

Description

This sequence change deletes 4 nucleotide in exon 5 of the MLH1 mRNA (c.404_407delTGAA), causing a frameshift at codon 135. This creates a premature translational stop signal (p.Leu135Glnfs*24) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 22, 2018