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

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 20, 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:
RCV001193208.2

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 colon cancer (HNPCC)
Synonyms:
Hereditary nonpolyposis colorectal cancer; Familial nonpolyposis colon cancer; Hereditary Nonpolyposis Colorectal Cancer Syndrome
Identifiers:
MONDO: MONDO:0018630; MedGen: C1333990; OMIM: PS120435

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001361914Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jun 20, 2022) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.

Lagerstedt Robinson K, Liu T, Vandrovcova J, Halvarsson B, Clendenning M, Frebourg T, Papadopoulos N, Kinzler KW, Vogelstein B, Peltomäki P, Kolodner RD, Nilbert M, Lindblom A.

J Natl Cancer Inst. 2007 Feb 21;99(4):291-9.

PubMed [citation]
PMID:
17312306
See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361914.2

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

Description

Variant summary: MLH1 c.677+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 4 computational tools predict a significant impact on normal splicing and abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250982 control chromosomes (gnomAD). The variant, c.677+1G>T, has been reported in the literature in individuals affected with Lynch Syndrome and early-onset colorectal cancer (examples: Parc_2003, Domingo_2004, Tanskanen_2013 and FerrerAvargues_2021). These data indicate that the variant is likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic

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

Last Updated: Sep 29, 2024