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NM_000179.3(MSH6):c.24C>G (p.Tyr8Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 21, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002427080.2

Allele description

NM_000179.3(MSH6):c.24C>G (p.Tyr8Ter)

Gene:
MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p16.3
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.24C>G (p.Tyr8Ter)
HGVS:
  • NC_000002.12:g.47783257C>G
  • NG_007111.1:g.5111C>G
  • NM_000179.3:c.24C>GMANE SELECT
  • NM_001281492.2:c.24C>G
  • NM_001281493.2:c.-713C>G
  • NP_000170.1:p.Tyr8Ter
  • NP_001268421.1:p.Tyr8Ter
  • LRG_219t1:c.24C>G
  • LRG_219:g.5111C>G
  • NC_000002.11:g.48010396C>G
  • NM_000179.2:c.24C>G
  • p.Tyr8X
Protein change:
Y8*
Links:
dbSNP: rs746306598
NCBI 1000 Genomes Browser:
rs746306598
Molecular consequence:
  • NM_001281493.2:c.-713C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000179.3:c.24C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001281492.2:c.24C>G - 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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002742739Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Likely pathogenic
(Dec 21, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV002742739.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.Y8* variant (also known as c.24C>G), located in coding exon 1 of the MSH6 gene, results from a C to G substitution at nucleotide position 24. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This alteration is identified in an individual whose rectal tumor demonstrated normal mismatch repair protein expression on immunohistochemistry (Ambry internal data). The predicted stop codon occurs in the 5’ end of theMSH6 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (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). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Feb 28, 2024