NM_000249.4(MLH1):c.1558+1G>A AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Mar 12, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000223493.2

Allele description [Variation Report for NM_000249.4(MLH1):c.1558+1G>A]

NM_000249.4(MLH1):c.1558+1G>A

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.1558+1G>A
HGVS:
  • NC_000003.12:g.37028933G>A
  • NG_007109.2:g.40584G>A
  • NM_000249.3:c.1558+1G>A
  • NM_000249.4:c.1558+1G>AMANE SELECT
  • NM_001167617.3:c.1264+1G>A
  • NM_001167618.3:c.835+1G>A
  • NM_001167619.3:c.835+1G>A
  • NM_001258271.2:c.1558+1G>A
  • NM_001258273.2:c.835+1G>A
  • NM_001258274.3:c.835+1G>A
  • NM_001354615.2:c.835+1G>A
  • NM_001354616.2:c.835+1G>A
  • NM_001354617.2:c.835+1G>A
  • NM_001354618.2:c.835+1G>A
  • NM_001354619.2:c.835+1G>A
  • NM_001354620.2:c.1264+1G>A
  • NM_001354621.2:c.535+1G>A
  • NM_001354622.2:c.535+1G>A
  • NM_001354623.2:c.535+1G>A
  • NM_001354624.2:c.484+1G>A
  • NM_001354625.2:c.484+1G>A
  • NM_001354626.2:c.484+1G>A
  • NM_001354627.2:c.484+1G>A
  • NM_001354628.2:c.1558+1G>A
  • NM_001354629.2:c.1459+1G>A
  • NM_001354630.2:c.1558+1G>A
  • LRG_216t1:c.1558+1G>A
  • LRG_216:g.40584G>A
  • NC_000003.11:g.37070424G>A
Links:
dbSNP: rs267607832
NCBI 1000 Genomes Browser:
rs267607832
Molecular consequence:
  • NM_000249.3:c.1558+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000249.4:c.1558+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167617.3:c.1264+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167618.3:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167619.3:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258271.2:c.1558+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258273.2:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258274.3:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354615.2:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354616.2:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354617.2:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354618.2:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354619.2:c.835+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354620.2:c.1264+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354621.2:c.535+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354622.2:c.535+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354623.2:c.535+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354624.2:c.484+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354625.2:c.484+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354626.2:c.484+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354627.2:c.484+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354628.2:c.1558+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354629.2:c.1459+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354630.2:c.1558+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
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; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000274273Ambry Geneticscriteria provided, single submitter
Pathogenic
(Mar 12, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Small bowel carcinoma in hereditary nonpolyposis colorectal cancer.

Benatti P, Roncucci L, Percesepe A, Viel A, Pedroni M, Tamassia MG, Vaccina F, Fante R, De Pietri S, Ponz de Leon M.

Am J Gastroenterol. 1998 Nov;93(11):2219-22.

PubMed [citation]
PMID:
9820400

Details of each submission

From Ambry Genetics, SCV000274273.5

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

Description

The c.1558+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the MLH1 gene. This alteration has been identified in individuals with a family history that met Amsterdam criteria for Lynch syndrome and/or showed loss of PMS2 protein expression by immunohistochemistry in their colorectal tumors (Ambry internal data). Another alteration at the same position, c.1558+1G>T, was identified in an Italian man whose family history met Amsterdam I criteria and his small bowel tumor showed high microsatellite instability (MSI-H). Functional studies using reverse transcriptase polymerase chain reaction (RT-PCR) revealed aberrant splicing in this patient due to the use of a cryptic splice site (Benatti P et al. Am. J. Gastroenterol., 1998 Nov;93:2219-22). In addition to the clinical data presented in the literature, 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: Oct 30, 2021

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