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NM_000249.4(MLH1):c.677+1G>T AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 19, 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:
RCV001034678.5

Allele description [Variation Report for NM_000249.4(MLH1):c.677+1G>T]

NM_000249.4(MLH1):c.677+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.677+1G>T
HGVS:
  • NC_000003.12:g.37012100G>T
  • NG_007109.2:g.23751G>T
  • NM_000249.4:c.677+1G>TMANE SELECT
  • NM_001167617.3:c.383+1G>T
  • NM_001167618.3:c.-47+1G>T
  • NM_001167619.3:c.-47+1G>T
  • NM_001258271.2:c.677+1G>T
  • NM_001258273.2:c.-47+1G>T
  • NM_001258274.3:c.-47+1G>T
  • NM_001354615.2:c.-47+1G>T
  • NM_001354616.2:c.-47+1G>T
  • NM_001354617.2:c.-47+1G>T
  • NM_001354618.2:c.-47+1G>T
  • NM_001354619.2:c.-47+1G>T
  • NM_001354620.2:c.383+1G>T
  • NM_001354621.2:c.-140+1G>T
  • NM_001354622.2:c.-253+1G>T
  • NM_001354623.2:c.-253+1G>T
  • NM_001354624.2:c.-150+1G>T
  • NM_001354625.2:c.-150+1G>T
  • NM_001354626.2:c.-150+1G>T
  • NM_001354627.2:c.-150+1G>T
  • NM_001354628.2:c.677+1G>T
  • NM_001354629.2:c.578+1G>T
  • NM_001354630.2:c.677+1G>T
  • LRG_216t1:c.677+1G>T
  • LRG_216:g.23751G>T
  • NC_000003.11:g.37053591G>T
  • NM_000249.3:c.677+1G>T
Links:
dbSNP: rs267607778
NCBI 1000 Genomes Browser:
rs267607778
Molecular consequence:
  • NM_000249.4:c.677+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167617.3:c.383+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167618.3:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167619.3:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258271.2:c.677+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258273.2:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258274.3:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354615.2:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354616.2:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354617.2:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354618.2:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354619.2:c.-47+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354620.2:c.383+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354621.2:c.-140+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354622.2:c.-253+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354623.2:c.-253+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354624.2:c.-150+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354625.2:c.-150+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354626.2:c.-150+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354627.2:c.-150+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354628.2:c.677+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354629.2:c.578+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354630.2:c.677+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
SCV000543594Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Apr 19, 2023) 		germlineclinical testing

PubMed (6)
[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

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]
PMID:
24362816
PMCID:
PMC4294709

Cancer risk in 348 French MSH2 or MLH1 gene carriers.

Parc Y, Boisson C, Thomas G, Olschwang S.

J Med Genet. 2003 Mar;40(3):208-13. No abstract available.

PubMed [citation]
PMID:
12624141
PMCID:
PMC1735402
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543594.6

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

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). ClinVar contains an entry for this variant (Variation ID: 90312). This variant is also known as IVS8+1G>T. Disruption of this splice site has been observed in individuals with a MLH1-related disease (PMID: 12624141, 15342696, 17312306, 27601186; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.

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

Last Updated: Sep 29, 2024