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NM_000249.4(MLH1):c.1896+1G>T AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 18, 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:
RCV000684807.6

Allele description [Variation Report for NM_000249.4(MLH1):c.1896+1G>T]

NM_000249.4(MLH1):c.1896+1G>T

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.1896+1G>T
HGVS:
  • NC_000003.12:g.37047684G>T
  • NG_007109.2:g.59335G>T
  • NM_000249.4:c.1896+1G>TMANE SELECT
  • NM_001167617.3:c.1602+1G>T
  • NM_001167618.3:c.1173+1G>T
  • NM_001167619.3:c.1173+1G>T
  • NM_001258271.2:c.1896+1G>T
  • NM_001258273.2:c.1173+1G>T
  • NM_001258274.3:c.1173+1G>T
  • NM_001354615.2:c.1173+1G>T
  • NM_001354616.2:c.1173+1G>T
  • NM_001354617.2:c.1173+1G>T
  • NM_001354618.2:c.1173+1G>T
  • NM_001354619.2:c.1173+1G>T
  • NM_001354620.2:c.1602+1G>T
  • NM_001354621.2:c.873+1G>T
  • NM_001354622.2:c.873+1G>T
  • NM_001354623.2:c.873+1G>T
  • NM_001354624.2:c.822+1G>T
  • NM_001354625.2:c.822+1G>T
  • NM_001354626.2:c.822+1G>T
  • NM_001354627.2:c.822+1G>T
  • NM_001354628.2:c.1896+1G>T
  • NM_001354629.2:c.1797+1G>T
  • NM_001354630.2:c.1732-833G>T
  • LRG_216t1:c.1896+1G>T
  • LRG_216:g.59335G>T
  • NC_000003.11:g.37089175G>T
  • NM_000249.3:c.1896+1G>T
Links:
dbSNP: rs267607867
NCBI 1000 Genomes Browser:
rs267607867
Molecular consequence:
  • NM_001354630.2:c.1732-833G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.1896+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167617.3:c.1602+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167618.3:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167619.3:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258271.2:c.1896+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258273.2:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258274.3:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354615.2:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354616.2:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354617.2:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354618.2:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354619.2:c.1173+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354620.2:c.1602+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354621.2:c.873+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354622.2:c.873+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354623.2:c.873+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354624.2:c.822+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354625.2:c.822+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354626.2:c.822+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354627.2:c.822+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354628.2:c.1896+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354629.2:c.1797+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000543560Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(May 18, 2023) 		germlineclinical testing

PubMed (8)
[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

Microsatellite instability is rare in rectal carcinomas and signifies hereditary cancer.

Nilbert M, Planck M, Fernebro E, Borg A, Johnson A.

Eur J Cancer. 1999 Jun;35(6):942-5.

PubMed [citation]
PMID:
10533476

Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families.

Wahlberg SS, Schmeits J, Thomas G, Loda M, Garber J, Syngal S, Kolodner RD, Fox E.

Cancer Res. 2002 Jun 15;62(12):3485-92.

PubMed [citation]
PMID:
12067992
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000543560.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 89926). Disruption of this splice site has been observed in individuals with Lynch syndrome (LS) or clinical features of LS (PMID: 10533476, 12067992, 15849733, 21642682; Invitae). This variant is present in population databases (rs267607867, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 16 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).

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

Last Updated: Aug 4, 2024