NM_000179.3(MSH6):c.1615CTT[1] (p.Leu540del) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Likely pathogenic (Last evaluated: Jun 26, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000685620.3

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:
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
SCV000813105Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 26, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

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

Tsai GJ, RaƱola 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

A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.

Thompson BA, Goldgar DE, Paterson C, Clendenning M, Walters R, Arnold S, Parsons MT, Michael D W, Gallinger S, Haile RW, Hopper JL, Jenkins MA, Lemarchand L, Lindor NM, Newcomb PA, Thibodeau SN; Colon Cancer Family Registry., Young JP, Buchanan DD, Tavtigian SV, Spurdle AB.

Hum Mutat. 2013 Jan;34(1):200-9. doi: 10.1002/humu.22213. Epub 2012 Oct 11.

PubMed [citation]
PMID:
22949379
PMCID:
PMC3538359
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000813105.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This variant, c.1618_1620del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Leu540del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a several individuals with clinical features of Lynch syndrome (PMID: 30374176, external communication). Moreover, it has been observed to be homozygous in an individual affected with clinical features of constitutional mismatch repair deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 419037). Based on a multifactorial likelihood algorithm using genetic, functional, and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Jul 29, 2021

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