NM_000249.4(MLH1):c.1990-1G>C AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Pathogenic (Last evaluated: Oct 12, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001036557.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1990-1G>C]

NM_000249.4(MLH1):c.1990-1G>C

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.1990-1G>C
HGVS:
  • NC_000003.12:g.37048903G>C
  • NG_007109.2:g.60554G>C
  • NM_000249.4:c.1990-1G>CMANE SELECT
  • NM_001167617.3:c.1696-1G>C
  • NM_001167618.3:c.1267-1G>C
  • NM_001167619.3:c.1267-1G>C
  • NM_001258271.2:c.1896+1220G>C
  • NM_001258273.2:c.1267-1G>C
  • NM_001258274.3:c.1267-1G>C
  • NM_001354615.2:c.1267-1G>C
  • NM_001354616.2:c.1267-1G>C
  • NM_001354617.2:c.1267-1G>C
  • NM_001354618.2:c.1267-1G>C
  • NM_001354619.2:c.1267-1G>C
  • NM_001354620.2:c.1696-1G>C
  • NM_001354621.2:c.967-1G>C
  • NM_001354622.2:c.967-1G>C
  • NM_001354623.2:c.967-1G>C
  • NM_001354624.2:c.916-1G>C
  • NM_001354625.2:c.916-1G>C
  • NM_001354626.2:c.916-1G>C
  • NM_001354627.2:c.916-1G>C
  • NM_001354628.2:c.1897-1G>C
  • NM_001354629.2:c.1891-1G>C
  • NM_001354630.2:c.1825-1G>C
  • LRG_216t1:c.1990-1G>C
  • LRG_216:g.60554G>C
  • NC_000003.11:g.37090394G>C
  • NM_000249.3:c.1990-1G>C
Links:
dbSNP: rs267607884
NCBI 1000 Genomes Browser:
rs267607884
Molecular consequence:
  • NM_001258271.2:c.1896+1220G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.1990-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167617.3:c.1696-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167618.3:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167619.3:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258273.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258274.3:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354615.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354616.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354617.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354618.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354619.2:c.1267-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354620.2:c.1696-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354621.2:c.967-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354622.2:c.967-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354623.2:c.967-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354624.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354625.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354626.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354627.2:c.916-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354628.2:c.1897-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354629.2:c.1891-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354630.2:c.1825-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001199927Invitaecriteria provided, single submitter
Pathogenic
(Oct 12, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Ten novel MSH2 and MLH1 germline mutations in families with HNPCC.

Krüger S, Bier A, Plaschke J, Höhl R, Aust DE, Kreuz FR, Pistorius SR, Saeger HD, Rothhammer V, Al-Taie O, Schackert HK.

Hum Mutat. 2004 Oct;24(4):351-2.

PubMed [citation]
PMID:
15365996

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001199927.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects an acceptor splice site in intron 17 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15365996, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 628266). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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: Nov 27, 2021

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