Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_007194.4(CHEK2):c.1627_1628insGTGCTGCTGTGT(p.Cys539_Val542dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L543L) has been classified as Likely benign.


Genomes: not found (cov: 32)


NM_007194.4 inframe_insertion


Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2


PhyloP100: 0.770
Variant links:
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

Very rare variant in population databases, with high coverage;
Nonframeshift variant in NON repetitive region in NM_007194.4.



Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHEK2NM_007194.4 linkuse as main transcriptc.1627_1628insGTGCTGCTGTGT p.Cys539_Val542dup inframe_insertion 15/15 ENST00000404276.6


Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHEK2ENST00000404276.6 linkuse as main transcriptc.1627_1628insGTGCTGCTGTGT p.Cys539_Val542dup inframe_insertion 15/151 NM_007194.4 P2O96017-1


GnomAD3 genomes
GnomAD4 exome
GnomAD4 genome


Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMay 07, 2018This variant, c.1616_1627dupGTGCTGCTGTGT, results in the insertion of 4 amino acids to the CHEK2 protein (p.Cys539_Val542dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 28, 2019- -

Computational scores

Source: dbNSFP v4.3

Calibrated prediction


Find out detailed SpliceAI scores and Pangolin per-transcript scores at



Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1569101939; hg19: chr22-29083889; API