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NM_000249.4(MLH1):c.677+1G>T AND Hereditary cancer-predisposing syndrome

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:
RCV002362711.3

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 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
SCV002662414Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 20, 2022) 		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 providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]
PMID:
27601186

Details of each submission

From Ambry Genetics, SCV002662414.3

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

Description

The c.677+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 8 of the MLH1 gene. This mutation, also referred to as IVS8+1G>T in published literature, has been reported in a family that met modified Amsterdam criteria (Parc Y et al. J Med Genet. 2003 Mar;40(3):208-13). This mutation was also detected in several individuals whose tumors showed high microsatellite instability and negative BRAF V600E analyses (Domingo E et al. J Med Genet. 2004 Sep;41(9):664-8; Lagerstedt Robinson K et al. J Natl Cancer Inst. 2007 Feb 21;99(4):291-9). This mutation has been identified in at least one proband who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability with loss of MLH1 expression by immunohistochemistry (IHC; Ambry internal data). Furthermore, this mutation has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024