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NM_000249.4(MLH1):c.2249dup (p.Tyr750Ter) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 4, 2018
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:
RCV000226996.5

Allele description [Variation Report for NM_000249.4(MLH1):c.2249dup (p.Tyr750Ter)]

NM_000249.4(MLH1):c.2249dup (p.Tyr750Ter)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.2249dup (p.Tyr750Ter)
HGVS:
  • NC_000003.12:g.37050631dup
  • NG_007109.2:g.62282dup
  • NG_053016.1:g.131187dup
  • NM_000249.4:c.2249dupMANE SELECT
  • NM_001167617.3:c.1955dup
  • NM_001167618.3:c.1526dup
  • NM_001167619.3:c.1526dup
  • NM_001258271.2:c.2042dup
  • NM_001258273.2:c.1526dup
  • NM_001258274.3:c.1526dup
  • NM_001354615.2:c.1526dup
  • NM_001354616.2:c.1526dup
  • NM_001354617.2:c.1526dup
  • NM_001354618.2:c.1526dup
  • NM_001354619.2:c.1526dup
  • NM_001354620.2:c.1955dup
  • NM_001354621.2:c.1226dup
  • NM_001354622.2:c.1226dup
  • NM_001354623.2:c.1226dup
  • NM_001354624.2:c.1175dup
  • NM_001354625.2:c.1175dup
  • NM_001354626.2:c.1175dup
  • NM_001354627.2:c.1175dup
  • NM_001354628.2:c.2156dup
  • NM_001354629.2:c.2150dup
  • NM_001354630.2:c.2084dup
  • NP_000240.1:p.Tyr750Ter
  • NP_001161089.1:p.Tyr652Ter
  • NP_001161090.1:p.Tyr509Ter
  • NP_001161091.1:p.Tyr509Ter
  • NP_001245200.1:p.Tyr681Ter
  • NP_001245202.1:p.Tyr509Ter
  • NP_001245203.1:p.Tyr509Ter
  • NP_001341544.1:p.Tyr509Ter
  • NP_001341545.1:p.Tyr509Ter
  • NP_001341546.1:p.Tyr509Ter
  • NP_001341547.1:p.Tyr509Ter
  • NP_001341548.1:p.Tyr509Ter
  • NP_001341549.1:p.Tyr652Ter
  • NP_001341550.1:p.Tyr409Ter
  • NP_001341551.1:p.Tyr409Ter
  • NP_001341552.1:p.Tyr409Ter
  • NP_001341553.1:p.Tyr392Ter
  • NP_001341554.1:p.Tyr392Ter
  • NP_001341555.1:p.Tyr392Ter
  • NP_001341556.1:p.Tyr392Ter
  • NP_001341557.1:p.Tyr719Ter
  • NP_001341558.1:p.Tyr717Ter
  • NP_001341559.1:p.Tyr695Ter
  • LRG_216:g.62282dup
  • NC_000003.11:g.37092121_37092122insA
  • NC_000003.11:g.37092122dup
  • NM_000249.3:c.2249dupA
Protein change:
Y392*
Links:
dbSNP: rs878853787
NCBI 1000 Genomes Browser:
rs878853787
Molecular consequence:
  • NM_000249.4:c.2249dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001167617.3:c.1955dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001167618.3:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001167619.3:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258271.2:c.2042dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258273.2:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001258274.3:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354615.2:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354616.2:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354617.2:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354618.2:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354619.2:c.1526dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354620.2:c.1955dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354621.2:c.1226dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354622.2:c.1226dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354623.2:c.1226dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354624.2:c.1175dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354625.2:c.1175dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354626.2:c.1175dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354627.2:c.1175dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354628.2:c.2156dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354629.2:c.2150dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354630.2:c.2084dup - 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
SCV000284054Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 4, 2018) 		germlineclinical testing

PubMed (12)
[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

N-terminus of hMLH1 confers interaction of hMutLalpha and hMutLbeta with hMutSalpha.

Plotz G, Raedle J, Brieger A, Trojan J, Zeuzem S.

Nucleic Acids Res. 2003 Jun 15;31(12):3217-26.

PubMed [citation]
PMID:
12799449
PMCID:
PMC162253

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns.

Borelli I, Casalis Cavalchini GC, Del Peschio S, Micheletti M, Venesio T, Sarotto I, Allavena A, Delsedime L, Barberis MA, Mandrile G, Berchialla P, Ogliara P, Bracco C, Pasini B.

Fam Cancer. 2014 Sep;13(3):401-13. doi: 10.1007/s10689-014-9726-3.

PubMed [citation]
PMID:
24802709
See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284054.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change results in a premature translational stop signal in the MLH1 gene (p.Tyr750*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 7 amino acids of the MLH1 protein. This truncation affects the highly conserved C-terminal domain responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). A different truncating variant downstream of this variant (p.Lys751Serfs*3) has been reported in individuals affected with Lynch syndrome and has been determined to be pathogenic (PMID: 24802709, 8797773, 27295708, 18566915, 18931482). This suggests that deletion of this region of the MLH1 protein is causative of disease. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). A different variant (c.2250C>G) giving rise to the same protein effect observed here (p.Tyr750*) has been reported in an individual affected with Lynch syndrome (PMID: 10422993). Experimental studies show that this change significantly affects PMS2-MLH1 dimerization and mismatch repair activity (PMID: 16338176, 20533529), indicating that this residue may be critical for protein function. This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 237334).

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

Last Updated: Sep 29, 2024