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

Clinical significance:Pathogenic (Last evaluated: Jun 14, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000533036.1

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

NM_000249.4(MLH1):c.677+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.677+1G>A
HGVS:
  • NC_000003.12:g.37012100G>A
  • NG_007109.2:g.23751G>A
  • NM_000249.4:c.677+1G>AMANE SELECT
  • NM_001167617.3:c.383+1G>A
  • NM_001167618.3:c.-47+1G>A
  • NM_001167619.3:c.-47+1G>A
  • NM_001258271.2:c.677+1G>A
  • NM_001258273.2:c.-47+1G>A
  • NM_001258274.3:c.-47+1G>A
  • NM_001354615.2:c.-47+1G>A
  • NM_001354616.2:c.-47+1G>A
  • NM_001354617.2:c.-47+1G>A
  • NM_001354618.2:c.-47+1G>A
  • NM_001354619.2:c.-47+1G>A
  • NM_001354620.2:c.383+1G>A
  • NM_001354621.2:c.-140+1G>A
  • NM_001354622.2:c.-253+1G>A
  • NM_001354623.2:c.-253+1G>A
  • NM_001354624.2:c.-150+1G>A
  • NM_001354625.2:c.-150+1G>A
  • NM_001354626.2:c.-150+1G>A
  • NM_001354627.2:c.-150+1G>A
  • NM_001354628.2:c.677+1G>A
  • NM_001354629.2:c.578+1G>A
  • NM_001354630.2:c.677+1G>A
  • LRG_216t1:c.677+1G>A
  • LRG_216:g.23751G>A
  • NC_000003.11:g.37053591G>A
  • NM_000249.3:c.677+1G>A
Links:
dbSNP: rs267607778
NCBI 1000 Genomes Browser:
rs267607778
Molecular consequence:
  • NM_000249.4:c.677+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167617.3:c.383+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167618.3:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001167619.3:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258271.2:c.677+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258273.2:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001258274.3:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354615.2:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354616.2:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354617.2:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354618.2:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354619.2:c.-47+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354620.2:c.383+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354621.2:c.-140+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354622.2:c.-253+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354623.2:c.-253+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354624.2:c.-150+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354625.2:c.-150+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354626.2:c.-150+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354627.2:c.-150+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354628.2:c.677+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354629.2:c.578+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354630.2:c.677+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
SCV000625183Invitaecriteria provided, single submitter
Pathogenic
(Jun 14, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000625183.1

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

Description

This sequence change affects a donor splice site in intron 8 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic. This particular variant has been reported in the literature in a family affected with Lynch syndrome (PMID: 12070261). A different variant affecting this nucleotide (c.677+1G>T) has been determined to be pathogenic (PMID: 27601186, 12624141, 15342696, 17312306). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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: Nov 27, 2021

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