NM_000251.2(MSH2):c.2680dup (p.Met894fs) AND Lynch syndrome

Clinical significance:Likely pathogenic (Last evaluated: Feb 7, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000614715.2

Allele description [Variation Report for NM_000251.2(MSH2):c.2680dup (p.Met894fs)]

NM_000251.2(MSH2):c.2680dup (p.Met894fs)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.2(MSH2):c.2680dup (p.Met894fs)
Other names:
p.Met894AsnfsX5
HGVS:
  • NC_000002.11:g.47709960_47709961insA
  • NC_000002.12:g.47482824dup
  • NG_007110.2:g.84701dup
  • NM_000251.3:c.2680dupMANE SELECT
  • NM_001258281.1:c.2482dup
  • NP_001245210.1:p.Met828fs
  • LRG_218t1:c.2680dup
  • LRG_218:g.84701dup
  • LRG_218p1:p.Met894fs
  • NC_000002.11:g.47709960_47709961insA
  • NC_000002.11:g.47709963_47709964insA
  • NC_000002.11:g.47709963dup
  • NM_000251.1:c.2680dupA
  • NM_000251.2:c.2680dupA
Protein change:
M828fs
Links:
dbSNP: rs876658211
NCBI 1000 Genomes Browser:
rs876658211
Molecular consequence:
  • NM_001258281.1:c.2482dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
2

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
SCV000731411Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Feb 7, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown22not providednot providednot providedclinical testing

Citations

PubMed

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]
PMID:
15713769
PMCID:
PMC2933041

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]
PMID:
27601186
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000731411.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (5)

Description

The p.Met894AsnfsX5 variant in MSH2 has been reported in at least 2 individuals with Lynch syndrome associated cancers (Casey 2005, Lagerstedt-Robinson 2016, Carter 2018). In addition, tumors sampled from 1 of these individuals lacked MSH2 and MSH6 expression. This variant has also been identified in 3/113586 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 894 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PM2, PS4_Supporting, PS3_Moderate.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not provided2not provided

Last Updated: Jul 7, 2021

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