NM_000249.4(MLH1):c.1558+1G>A AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Pathogenic (Last evaluated: Aug 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000204627.5

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_000249.4: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
  • NM_000249.3:c.1558+1G>A
Links:
dbSNP: rs267607832
NCBI 1000 Genomes Browser:
rs267607832
Molecular consequence:
  • 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]

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
SCV000260539Invitaecriteria provided, single submitter
Pathogenic
(Aug 24, 2020)
germlineclinical testing

PubMed (6)
[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

Hereditary nonpolyposis colorectal cancer: an approach to the selection of candidates to genetic testing based on clinical and molecular characteristics.

Viel A, Genuardi M, Lucci-Cordisco E, Capozzi E, Rovella V, Fornasarig M, Ponz de Leòn M, Anti M, Pedroni M, Bellacosa A, Percesepe A, Covino M, Benatti P, Del Tin L, Roncucci L, Valentini M, Boiocchi M, Neri G.

Community Genet. 1998;1(4):229-36.

PubMed [citation]
PMID:
15178966

Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation.

Lastella P, Patruno M, Forte G, Montanaro A, Di Gregorio C, Sabbà C, Suppressa P, Piepoli A, Panza A, Andriulli A, Resta N, Stella A.

Fam Cancer. 2011 Jun;10(2):285-95. doi: 10.1007/s10689-011-9419-0.

PubMed [citation]
PMID:
21286823
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000260539.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change affects a donor splice site in intron 13 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 several individuals affected with Lynch syndrome (PMID: 15178966, 21286823). This splice site has also been reported as IVS13+1G in the literature. ClinVar contains an entry for this variant (Variation ID: 220185). 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: Dec 2, 2021

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