NM_007194.4(CHEK2):c.417C>A (p.Tyr139Ter) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic (Last evaluated: Apr 4, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_007194.4(CHEK2):c.417C>A (p.Tyr139Ter)]

NM_007194.4(CHEK2):c.417C>A (p.Tyr139Ter)

CHEK2:checkpoint kinase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_007194.4(CHEK2):c.417C>A (p.Tyr139Ter)
  • NC_000022.11:g.28725270G>T
  • NG_008150.1:g.21565C>A
  • NG_008150.2:g.21597C>A
  • NM_001005735.2:c.546C>A
  • NM_001257387.2:c.-361C>A
  • NM_001349956.2:c.417C>A
  • NM_007194.4:c.417C>AMANE SELECT
  • NM_145862.2:c.417C>A
  • NP_001005735.1:p.Tyr182Ter
  • NP_001336885.1:p.Tyr139Ter
  • NP_009125.1:p.Tyr139Ter
  • NP_665861.1:p.Tyr139Ter
  • LRG_302t1:c.417C>A
  • LRG_302:g.21597C>A
  • LRG_302p1:p.Tyr139Ter
  • NC_000022.10:g.29121258G>T
  • NM_007194.3:c.417C>A
  • p.Tyr139*
Protein change:
dbSNP: rs200917541
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001257387.2:c.-361C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001005735.2:c.546C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001349956.2:c.417C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_007194.4:c.417C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_145862.2:c.417C>A - nonsense - [Sequence Ontology: SO:0001587]


Hereditary breast and ovarian cancer syndrome (HBOC)
Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC)
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001572499Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
(Apr 4, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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



Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.

Sun J, Meng H, Yao L, Lv M, Bai J, Zhang J, Wang L, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y.

Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. doi: 10.1158/1078-0432.CCR-16-3227. Epub 2017 Jul 19.

PubMed [citation]

Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome.

Yoo J, Lee GD, Kim JH, Lee SN, Chae H, Han E, Kim Y, Kim M.

Ann Lab Med. 2020 Mar;40(2):148-154. doi: 10.3343/alm.2020.40.2.148.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001572499.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)


Variant summary: CHEK2 c.417C>A (p.Tyr139X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251288 control chromosomes. c.417C>A has been reported in the literature in multiple individuals affected with breast cancer (example, Sun_2017) and co-segregating with papillary thyroid cancer in at-least one large family (Zhao_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced p53 phosphorylation and decreased p53 protein level (Zho_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 7, 2021

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