NM_000251.2(MSH2):c.2680dup (p.Met894fs) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 11, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000214664.4

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:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000273149Ambry Geneticscriteria provided, single submitter
Pathogenic
(Sep 11, 2020)
germlineclinical testing

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

Citation Link,

SCV000908332Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jun 16, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000273149.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The c.2680dupA pathogenic mutation, located in coding exon 16 of the MSH2 gene, results from a duplication of one nucleotide at position c.2680 resulting in a translational frameshift with a predicted alternate stop codon (p.M894Nfs*5). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been detected in multiple individuals diagnosed with colorectal cancer that demonstrated either high microsatellite instability (MSI-H) or absent MSH2 and/or MSH6 staining by immunohistochemistry (IHC) (Ambry internal data; Casey G et al. JAMA 2005 Feb; 293(7):799-809). As such, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000908332.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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