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NM_000251.3(MSH2):c.70C>T (p.Gln24Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Oct 18, 2023
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000772129.7

Allele description [Variation Report for NM_000251.3(MSH2):c.70C>T (p.Gln24Ter)]

NM_000251.3(MSH2):c.70C>T (p.Gln24Ter)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.70C>T (p.Gln24Ter)
Other names:
p.Q24*:CAG>TAG
HGVS:
  • NC_000002.12:g.47403261C>T
  • NG_007110.2:g.5138C>T
  • NM_000251.3:c.70C>TMANE SELECT
  • NM_001258281.1:c.-31+86C>T
  • NP_000242.1:p.Gln24Ter
  • NP_000242.1:p.Gln24Ter
  • LRG_218t1:c.70C>T
  • LRG_218:g.5138C>T
  • LRG_218p1:p.Gln24Ter
  • NC_000002.11:g.47630400C>T
  • NM_000251.1:c.70C>T
  • NM_000251.2:c.70C>T
  • p.Gln24Stop
Protein change:
Q24*
Links:
dbSNP: rs587779976
NCBI 1000 Genomes Browser:
rs587779976
Molecular consequence:
  • NM_001258281.1:c.-31+86C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000251.3:c.70C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000905217Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jun 2, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001188342Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Oct 18, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

The predicted truncation from a cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex.

Cyr JL, Brown GD, Stroop J, Heinen CD.

Mol Carcinog. 2012 Aug;51(8):647-58. doi: 10.1002/mc.20838. Epub 2011 Aug 11.

PubMed [citation]
PMID:
21837758
PMCID:
PMC3220760

The rules and impact of nonsense-mediated mRNA decay in human cancers.

Lindeboom RG, Supek F, Lehner B.

Nat Genet. 2016 Oct;48(10):1112-8. doi: 10.1038/ng.3664. Epub 2016 Sep 12.

PubMed [citation]
PMID:
27618451
PMCID:
PMC5045715
See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000905217.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This variant changes 1 nucleotide in exon 1 of the MSH2 gene, creating a premature translation stop signal. However this variant may escape nonsense-mediated mRNA decay due to secondary initiation at one of multiple downstream AUG start codons. Experimental studies have shown that a protein with a deletion of 25 amino acids of the N-terminal domain has been observed as partially functional (PMID: 21837758). An alternative MSH2 transcript (NM_001258281) lacking the first 66 amino acids of the primary transcript, is expressed at similar or higher levels in human tissues (https://gnomad.broadinstitute.org/). Premature stop codons located in close proximity to the canonical Met1 start codon often show a decrease in nonsense-mediated mRNA decay efficiency (PMID: 27618451). Missense variants impacting the start codon at Met1 are classified as VUS (ClinVar Variation ID: 90832, 90833, 230889). This variant has been reported in individuals affected with endometrial and peritoneal cancer (PMID: 26681312), ovarian cancer (PMID: 30322717), and early-onset colorectal cancer (PMID: 31068090). 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). The clinical impact of truncations in MSH2 prior to a secondary in-frame methionine at amino acid residue 26 is not fully understood at this time. Until further functional and clinical evidence is obtained, based on the evidence available this variant is classified as Likely Pathogenic.

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

From Ambry Genetics, SCV001188342.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The p.Q24* variant (also known as c.70C>T), located in coding exon 1 of the MSH2 gene, results from a C to T substitution at nucleotide position 70. This changes the amino acid from a glutamine to a stop codon within coding exon 1. The predicted stop codon occurs within the first 150 nucleotides of the MSH2 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation through use of a downstream, in-frame AUG at codon 26 (Farrington SM et al. Am J Hum Genet, 1998 Sep;63:749-59; Kets CM et al. Eur J Hum Genet, 2009 Feb;17:159-64; Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, MutS alpha complexes formed using recombinantly expressed wild type MSH6 and MSH2 with a deletion of the first 25 amino acids of the protein, demonstrated partially retained function in several biochemical assays that measured ATP binding, ATPase activity, mismatch binding, and sliding clamp formation (Cyr JL et al. Mol Carcinog, 2012 Aug;51:647-58). This alteration was identified in a patient diagnosed with both endometrial and peritoneal cancers (Susswein LR et al. Genet. Med. 2016 08;18:823-32). This variant was also identified once in a cohort of women with ovarian cancer undergoing multigene panel testing, once in a cohort of women undergoing multigene panel testing for hereditary cancer risk, and in a proband diagnosed with colorectal cancer at age 41 with a family history of colorectal cancer in one first degree relative (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Ricci MT et al. Tumori, 2019 Aug;105:338-352). In addition, this variant has been identified in a proband whose colorectal tumor demonstrated normal staining for MSH2, MLH1, and MSH6 proteins on immunohistochemistry (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

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

Last Updated: Sep 29, 2024