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NM_000249.4(MLH1):c.67G>T (p.Glu23Ter) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 25, 2023
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:
RCV000811317.6

Allele description [Variation Report for NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)]

NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.67G>T (p.Glu23Ter)
Other names:
p.E23*:GAA>TAA
HGVS:
  • NC_000003.12:g.36993614G>T
  • NG_007109.2:g.5265G>T
  • NG_008418.1:g.4691C>A
  • NM_000249.4:c.67G>TMANE SELECT
  • NM_001167617.3:c.-450G>T
  • NM_001167618.3:c.-879G>T
  • NM_001167619.3:c.-792G>T
  • NM_001258271.2:c.67G>T
  • NM_001258273.2:c.-566G>T
  • NM_001258274.3:c.-1029G>T
  • NM_001354615.2:c.-560G>T
  • NM_001354616.2:c.-560G>T
  • NM_001354617.2:c.-652G>T
  • NM_001354618.2:c.-884G>T
  • NM_001354619.2:c.-1008G>T
  • NM_001354620.2:c.-218G>T
  • NM_001354621.2:c.-977G>T
  • NM_001354622.2:c.-1090G>T
  • NM_001354623.2:c.-999G>T
  • NM_001354624.2:c.-760G>T
  • NM_001354625.2:c.-658G>T
  • NM_001354626.2:c.-755G>T
  • NM_001354627.2:c.-987G>T
  • NM_001354628.2:c.67G>T
  • NM_001354629.2:c.67G>T
  • NM_001354630.2:c.67G>T
  • NP_000240.1:p.Glu23Ter
  • NP_000240.1:p.Glu23Ter
  • NP_001245200.1:p.Glu23Ter
  • NP_001341557.1:p.Glu23Ter
  • NP_001341558.1:p.Glu23Ter
  • NP_001341559.1:p.Glu23Ter
  • LRG_216t1:c.67G>T
  • LRG_216:g.5265G>T
  • LRG_216p1:p.Glu23Ter
  • NC_000003.11:g.37035105G>T
  • NM_000249.3:c.67G>T
Protein change:
E23*
Links:
dbSNP: rs63750823
NCBI 1000 Genomes Browser:
rs63750823
Molecular consequence:
  • NM_001167617.3:c.-450G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-879G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-792G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-566G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-1029G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-560G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-560G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-652G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-884G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-1008G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-218G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-977G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-1090G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-999G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-760G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-658G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-755G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-987G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258271.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354628.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354629.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354630.2:c.67G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MeSH: D003123; MedGen: C0009405

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000951577Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(May 25, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]
PMID:
24362816
PMCID:
PMC4294709
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000951577.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Glu23*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 90331). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 11754112, 15849733, 16736291, 26681312). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).

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

Last Updated: Sep 29, 2024