U.S. flag

An official website of the United States government

NM_000249.4(MLH1):c.1896+1G>T AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 25, 2022
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:
RCV001013523.4

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 cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001174121Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 25, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

Details of each submission

From Ambry Genetics, SCV001174121.4

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

Description

The c.1896+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 16 of the MLH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation has been detected in multiple individuals meeting Bethesda criteria whose tumors showed high microsatellite instability (Planck M et al. Int J Cancer. 1999 Oct 8;83(2):197-202; Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702; Nilbert M et al. Eur. J. Cancer, 1999 Jun;35:942-5), and in multiple individuals whose tumors were absent for MLH1 and PMS2 on immunohistochemistry (Ambry internal data). As such, this alteration is classified as a disease-causing mutation.

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

Last Updated: Oct 8, 2024