NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del) AND Lynch syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 18, 2018)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000515764.3

Allele description [Variation Report for NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)]

NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del)
HGVS:
  • NC_000002.12:g.47799598CTT[1]
  • NG_007111.1:g.21452CTT[1]
  • NM_000179.3:c.1615CTT[1]MANE SELECT
  • NM_001281492.2:c.1225CTT[1]
  • NM_001281493.2:c.709CTT[1]
  • NM_001281494.2:c.709CTT[1]
  • NP_000170.1:p.Leu540del
  • NP_001268421.1:p.Leu410del
  • NP_001268422.1:p.Leu238del
  • NP_001268423.1:p.Leu238del
  • LRG_219:g.21452CTT[1]
  • NC_000002.11:g.48026736_48026738del
  • NC_000002.11:g.48026737CTT[1]
  • NM_000179.2:c.1618_1620delCTT
Protein change:
L238del
Links:
dbSNP: rs1064793600
NCBI 1000 Genomes Browser:
rs1064793600
Molecular consequence:
  • NM_000179.3:c.1615CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001281492.2:c.1225CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001281493.2:c.709CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_001281494.2:c.709CTT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000611879University of Washington Department of Laboratory Medicine, University of Washingtoncriteria provided, single submitter
Pathogenic
(Mar 28, 2018)
germlineresearch

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

SCV000920456International Society for Gastrointestinal Hereditary Tumours (InSiGHT)reviewed by expert panel
Pathogenic
(Oct 18, 2018)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Citations

PubMed

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]
PMID:
30374176

Details of each submission

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000611879.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providedyesresearch PubMed (1)

Description

The MSH6 variant designated as NM_000179.2:c.1618_1620del (p.Leu540del) is classified as pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood of 1.838 to 1, which supports pathogenicity (Thompson et al, 2003, PMID:12900794). In addition, endometrial and colorectal tumors from an affected individual in the family contained the germline MHS6 p.Leu540del variant. Each tumor had microsatellite instability and had a different independent second heterozygous pathogenic mutation in MSH6. Each of these observations supports classification of pathogenicity. In addition, this variant has previously been reported in two MSI high tumors with lack of MSH6 staining on IHC (http://www.umd.be/). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives over 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH6 function and increase cancer risk. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot provided1not provided

From International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000920456.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Multifactorial likelihood analysis posterior probability > 0.99 (0.992)

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

Last Updated: Jul 29, 2021

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