NM_000249.4(MLH1):c.860del (p.Asn287fs) AND Lynch syndrome

Clinical significance:Pathogenic (Last evaluated: Sep 5, 2013)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000075891.3

Allele description [Variation Report for NM_000249.4(MLH1):c.860del (p.Asn287fs)]

NM_000249.4(MLH1):c.860del (p.Asn287fs)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.860del (p.Asn287fs)
HGVS:
  • NC_000003.12:g.37017575del
  • NG_007109.2:g.29226del
  • NM_000249.4:c.860delMANE SELECT
  • NM_001167617.3:c.566del
  • NM_001167618.3:c.137del
  • NM_001167619.3:c.137del
  • NM_001258271.2:c.860del
  • NM_001258273.2:c.137del
  • NM_001258274.3:c.137del
  • NM_001354615.2:c.137del
  • NM_001354616.2:c.137del
  • NM_001354617.2:c.137del
  • NM_001354618.2:c.137del
  • NM_001354619.2:c.137del
  • NM_001354620.2:c.566del
  • NM_001354621.2:c.-139-2735del
  • NM_001354622.2:c.-139-2735del
  • NM_001354623.2:c.-139-2735del
  • NM_001354624.2:c.-37+3031del
  • NM_001354625.2:c.-37+3031del
  • NM_001354626.2:c.-37+3031del
  • NM_001354627.2:c.-37+3031del
  • NM_001354628.2:c.860del
  • NM_001354629.2:c.761del
  • NM_001354630.2:c.860del
  • NP_000240.1:p.Asn287fs
  • NP_001161089.1:p.Asn189fs
  • NP_001161090.1:p.Asn46fs
  • NP_001161091.1:p.Asn46fs
  • NP_001245200.1:p.Asn287fs
  • NP_001245202.1:p.Asn46fs
  • NP_001245203.1:p.Asn46fs
  • NP_001341544.1:p.Asn46fs
  • NP_001341545.1:p.Asn46fs
  • NP_001341546.1:p.Asn46fs
  • NP_001341547.1:p.Asn46fs
  • NP_001341548.1:p.Asn46fs
  • NP_001341549.1:p.Asn189fs
  • NP_001341557.1:p.Asn287fs
  • NP_001341558.1:p.Asn254fs
  • NP_001341559.1:p.Asn287fs
  • LRG_216:g.29226del
  • NC_000003.11:g.37059066del
  • NM_000249.3:c.860delA
Protein change:
N189fs
Links:
dbSNP: rs63750034
NCBI 1000 Genomes Browser:
rs63750034
Molecular consequence:
  • NM_000249.4:c.860del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001167617.3:c.566del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001167618.3:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001167619.3:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258271.2:c.860del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258273.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258274.3:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354615.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354616.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354617.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354618.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354619.2:c.137del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354620.2:c.566del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354628.2:c.860del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354629.2:c.761del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354630.2:c.860del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354621.2:c.-139-2735del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354622.2:c.-139-2735del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-139-2735del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354624.2:c.-37+3031del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-37+3031del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-37+3031del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-37+3031del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Lynch syndrome
Synonyms:
Familial nonpolyposis colon cancer
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100; OMIM: PS120435

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000106907International Society for Gastrointestinal Hereditary Tumours (InSiGHT)reviewed by expert panel
Pathogenic
(Sep 5, 2013)
germlineresearch

Citation Link,

SCV000917652Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Jun 5, 2018)
germlineclinical testing

Citation Link

Description

SCV000106907

Summary from all submissions

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

Details of each submission

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106907.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided

Description

Coding sequence variation resulting in a stop codon

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917652.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: MLH1 c.860delA (p.Asn287ThrfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (eg. c.927dupC, 1210_1211delCT and c.1489dupC). The variant was absent in 246256 control chromosomes. To our knowledge, no occurrence of c.860delA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, but two locus specific databases cite the variant as "causative". Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Nov 27, 2021

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