NM_000249.4(MLH1):c.454-1G>C AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 9, 2019
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:
RCV000568411.3

Allele description [Variation Report for NM_000249.4(MLH1):c.454-1G>C]

NM_000249.4(MLH1):c.454-1G>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.454-1G>C
HGVS:
  • NC_000003.12:g.37008813G>C
  • NG_007109.2:g.20464G>C
  • NM_000249.4:c.454-1G>CMANE SELECT
  • NM_001167617.3:c.160-1G>C
  • NM_001167618.3:c.-270-1G>C
  • NM_001167619.3:c.-179+1750G>C
  • NM_001258271.2:c.454-1G>C
  • NM_001258273.2:c.-270-1G>C
  • NM_001258274.3:c.-270-1G>C
  • NM_001354615.2:c.-179+1750G>C
  • NM_001354616.2:c.-179+1750G>C
  • NM_001354617.2:c.-270-1G>C
  • NM_001354618.2:c.-270-1G>C
  • NM_001354619.2:c.-270-1G>C
  • NM_001354620.2:c.160-1G>C
  • NM_001354621.2:c.-363-1G>C
  • NM_001354622.2:c.-476-1G>C
  • NM_001354623.2:c.-476-1G>C
  • NM_001354624.2:c.-373-1G>C
  • NM_001354625.2:c.-282+1750G>C
  • NM_001354626.2:c.-373-1G>C
  • NM_001354627.2:c.-373-1G>C
  • NM_001354628.2:c.454-1G>C
  • NM_001354629.2:c.355-1G>C
  • NM_001354630.2:c.454-1G>C
  • LRG_216t1:c.454-1G>C
  • LRG_216:g.20464G>C
  • NC_000003.11:g.37050304G>C
  • NM_000249.3:c.454-1G>C
Links:
dbSNP: rs193922370
NCBI 1000 Genomes Browser:
rs193922370
Molecular consequence:
  • NM_001167619.3:c.-179+1750G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354615.2:c.-179+1750G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354616.2:c.-179+1750G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-282+1750G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.454-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167617.3:c.160-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001167618.3:c.-270-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258271.2:c.454-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258273.2:c.-270-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001258274.3:c.-270-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354617.2:c.-270-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354618.2:c.-270-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354619.2:c.-270-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354620.2:c.160-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354621.2:c.-363-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354622.2:c.-476-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354623.2:c.-476-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354624.2:c.-373-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354626.2:c.-373-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354627.2:c.-373-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354628.2:c.454-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354629.2:c.355-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354630.2:c.454-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
1

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000676057Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Dec 9, 2019) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene.

Wagner A, Barrows A, Wijnen JT, van der Klift H, Franken PF, Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan-Changur S, Breukel C, Meijers-Heijboer H, Morreau H, van Puijenbroek M, Burn J, Coronel S, Kinarski Y, Okimoto R, Watson P, Lynch JF, de la Chapelle A, Lynch HT, Fodde R.

Am J Hum Genet. 2003 May;72(5):1088-100. Epub 2003 Mar 25.

PubMed [citation]
PMID:
12658575
PMCID:
PMC1180263

Details of each submission

From Ambry Genetics, SCV000676057.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The c.454-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the MLH1 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect involving exons excluded from naturally occurring transcripts; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Mar 5, 2024