NM_000251.2(MSH2):c.2335dup (p.Met779fs) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Jan 15, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000490902.2

Allele description [Variation Report for NM_000251.2(MSH2):c.2335dup (p.Met779fs)]

NM_000251.2(MSH2):c.2335dup (p.Met779fs)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.2(MSH2):c.2335dup (p.Met779fs)
HGVS:
  • NC_000002.12:g.47478396dup
  • NG_007110.2:g.80273dup
  • NM_000251.2:c.2335dup
  • NM_001258281.1:c.2137dup
  • NP_000242.1:p.Met779fs
  • NP_001245210.1:p.Met713fs
  • LRG_218t1:c.2335dup
  • LRG_218:g.80273dup
  • LRG_218p1:p.Met779fs
  • NC_000002.11:g.47705534_47705535insA
  • NC_000002.11:g.47705535dup
  • NM_000251.1:c.2335dup
  • NM_000251.1:c.2335dupA
  • NM_000251.2:c.2335dupA
Protein change:
M713fs
Links:
dbSNP: rs63750149
NCBI 1000 Genomes Browser:
rs63750149
Molecular consequence:
  • NM_000251.2:c.2335dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258281.1:c.2137dup - 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
SCV000580605Ambry Geneticscriteria provided, single submitter
Pathogenic
(Jun 1, 2018)
germlineclinical testing

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

Citation Link,

SCV001359867Color Health, Inccriteria provided, single submitter
Pathogenic
(Jan 15, 2020)
germlineclinical testing

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

Description

This variant inserts 1 nucleotide in exon 14 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

SCV001359867

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Reduction in hMSH2 mRNA levels by premature translation termination: implications for mutation screening in hereditary nonpolyposis colorectal cancer.

Lin X, Choi JH, Lynch P, Xi L, Wu E, Frazier ML.

Dig Dis Sci. 1999 Mar;44(3):553-9.

PubMed [citation]
PMID:
10080150

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, SCV000580605.4

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

Description

The c.2335dupA pathogenic mutation, located in coding exon 14 of the MSH2 gene, results from a duplication of A at nucleotide position 2335, causing a translational frameshift with a predicted alternate stop codon (p.M779Nfs*8). This pathogenic mutation has been reported in a patient meeting Amsterdam criteria for HNPCC (Lin X et al. Dig. Dis. Sci. 1999 Mar;44:553-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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, SCV001359867.1

#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: Aug 27, 2021

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