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NM_000249.4(MLH1):c.677+5G>A AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 11, 2024
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:
RCV000985788.3

Allele description [Variation Report for NM_000249.4(MLH1):c.677+5G>A]

NM_000249.4(MLH1):c.677+5G>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.677+5G>A
HGVS:
  • NC_000003.12:g.37012104G>A
  • NG_007109.2:g.23755G>A
  • NM_000249.4:c.677+5G>AMANE SELECT
  • NM_001167617.3:c.383+5G>A
  • NM_001167618.3:c.-47+5G>A
  • NM_001167619.3:c.-47+5G>A
  • NM_001258271.2:c.677+5G>A
  • NM_001258273.2:c.-47+5G>A
  • NM_001258274.3:c.-47+5G>A
  • NM_001354615.2:c.-47+5G>A
  • NM_001354616.2:c.-47+5G>A
  • NM_001354617.2:c.-47+5G>A
  • NM_001354618.2:c.-47+5G>A
  • NM_001354619.2:c.-47+5G>A
  • NM_001354620.2:c.383+5G>A
  • NM_001354621.2:c.-140+5G>A
  • NM_001354622.2:c.-253+5G>A
  • NM_001354623.2:c.-253+5G>A
  • NM_001354624.2:c.-150+5G>A
  • NM_001354625.2:c.-150+5G>A
  • NM_001354626.2:c.-150+5G>A
  • NM_001354627.2:c.-150+5G>A
  • NM_001354628.2:c.677+5G>A
  • NM_001354629.2:c.578+5G>A
  • NM_001354630.2:c.677+5G>A
  • LRG_216t1:c.677+5G>A
  • LRG_216:g.23755G>A
  • NC_000003.11:g.37053595G>A
  • NM_000249.3:c.677+5G>A
Links:
dbSNP: rs587779034
NCBI 1000 Genomes Browser:
rs587779034
Molecular consequence:
  • NM_000249.4:c.677+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167617.3:c.383+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167618.3:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001167619.3:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258271.2:c.677+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258273.2:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258274.3:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354615.2:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354616.2:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354617.2:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354618.2:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354619.2:c.-47+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354620.2:c.383+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354621.2:c.-140+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354622.2:c.-253+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-253+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354624.2:c.-150+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-150+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-150+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-150+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354628.2:c.677+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354629.2:c.578+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354630.2:c.677+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001134321Quest Diagnostics Nichols Institute San Juan Capistrano
criteria provided, single submitter

(Quest Diagnostics criteria)		pathogenic
(Sep 11, 2024) 		unknownclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

MLH1 intronic variants mapping to + 5 position of splice donor sites lead to deleterious effects on RNA splicing.

Piñero TA, Soukarieh O, Rolain M, Alvarez K, López-Köstner F, Torrezan GT, Carraro DM, De Oliveira Nascimento IL, Bomfim TF, Machado-Lopes TMB, Freitas JC, Toralles MB, Sandes KA, Rossi BM, Junior SA, Meira J, Dominguez-Valentin M, Møller P, Vaccaro CA, Martins A, Pavicic WH.

Fam Cancer. 2020 Oct;19(4):323-336. doi: 10.1007/s10689-020-00182-5.

PubMed [citation]
PMID:
32363481

MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome.

Dominguez-Valentin M, Wernhoff P, Cajal AR, Kalfayan PG, Piñero TA, Gonzalez ML, Ferro A, Sammartino I, Causada Calo NS, Vaccaro CA.

Front Oncol. 2016;6:189. doi: 10.3389/fonc.2016.00189. No abstract available.

PubMed [citation]
PMID:
27606285
PMCID:
PMC4996012
See all PubMed Citations (8)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134321.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The MLH1 c.677+5G>A variant has been reported in the published literature in a small number of Lynch syndrome families (PMIDs: 24344984 (2013), 27606285 (2016), 28874130 (2017)). Splicing studies using minigenes and patient RNA have shown that this variant causes the skipping of exon 8 that results in a frameshift in the coding sequence of the MLH1 mRNA and reduces the amount of MLH1 protein (PMID: 32363481 (2020)). Family studies have also shown that this variant co-segregates with disease, including colorectal cancer (PMID: 32363481 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

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

Last Updated: Sep 29, 2024