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NM_000249.4(MLH1):c.67del (p.Glu23fs) AND Hereditary nonpolyposis colon cancer

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 5, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001193211.1

Allele description [Variation Report for NM_000249.4(MLH1):c.67del (p.Glu23fs)]

NM_000249.4(MLH1):c.67del (p.Glu23fs)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.67del (p.Glu23fs)
HGVS:
  • NC_000003.12:g.36993614del
  • NG_007109.2:g.5265del
  • NG_008418.1:g.4695del
  • NM_000249.4:c.67delMANE SELECT
  • NM_001167617.3:c.-450del
  • NM_001167618.3:c.-879del
  • NM_001167619.3:c.-792del
  • NM_001258271.2:c.67del
  • NM_001258273.2:c.-566del
  • NM_001258274.3:c.-1029del
  • NM_001354615.2:c.-560del
  • NM_001354616.2:c.-560del
  • NM_001354617.2:c.-652del
  • NM_001354618.2:c.-884del
  • NM_001354619.2:c.-1008del
  • NM_001354620.2:c.-218del
  • NM_001354621.2:c.-977del
  • NM_001354622.2:c.-1090del
  • NM_001354623.2:c.-999del
  • NM_001354624.2:c.-760del
  • NM_001354625.2:c.-658del
  • NM_001354626.2:c.-755del
  • NM_001354627.2:c.-987del
  • NM_001354628.2:c.67del
  • NM_001354629.2:c.67del
  • NM_001354630.2:c.67del
  • NP_000240.1:p.Glu23fs
  • NP_001245200.1:p.Glu23fs
  • NP_001341557.1:p.Glu23fs
  • NP_001341558.1:p.Glu23fs
  • NP_001341559.1:p.Glu23fs
  • LRG_216:g.5265del
  • NC_000003.11:g.37035101del
  • NC_000003.11:g.37035105del
  • NM_000249.3:c.67delG
Protein change:
E23fs
Links:
dbSNP: rs63750822
NCBI 1000 Genomes Browser:
rs63750822
Molecular consequence:
  • NM_001167617.3:c.-450del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-879del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-792del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-566del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-1029del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-560del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-560del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-652del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-884del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-1008del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-218del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-977del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-1090del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-999del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-760del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-658del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-755del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-987del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258271.2:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354628.2:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354629.2:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354630.2:c.67del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Hereditary nonpolyposis colon cancer (HNPCC)
Synonyms:
Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:
MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001361917Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Sep 5, 2019) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]
PMID:
15713769
PMCID:
PMC2933041

Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome.

Rouleau E, Lefol C, Bourdon V, Coulet F, Noguchi T, Soubrier F, Bièche I, Olschwang S, Sobol H, Lidereau R.

Hum Mutat. 2009 Jun;30(6):867-75. doi: 10.1002/humu.20947.

PubMed [citation]
PMID:
19224586
See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361917.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: MLH1 c.67delG (p.Glu23LysfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251404 control chromosomes (gnomAD). c.67delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (LS) or LS related cancers (e.g. Domingo _2004, Ferguson_2014, Dymerska_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. The variant has also been classified by an expert panel (InSiGHT) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024