rs587782684

Positions:

• chr22-28687961-CG-C
• chr22-28687961-CG-CGG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_007194.4(CHEK2):​c.1567delC​(p.Arg523fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:11
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0398 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1567delC	p.Arg523fs	frameshift_variant	15/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1567delC	p.Arg523fs	frameshift_variant	15/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3 AN: 152144 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000104 AC: 15 AN: 1443906 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 10 AN XY: 718682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000197 AC: 3 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change results in a frameshift in the CHEK2 gene (p.Arg523Valfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the CHEK2 protein and extend the protein by 21 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This frameshift has been observed in individual(s) with ovarian cancer (PMID: 28888541). ClinVar contains an entry for this variant (Variation ID: 142737). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. The last exon of the CHEK2 gene contains coding sequences for a nuclear localization signal (NLS, residues 515-522), which is necessary for CHEK2 cellular functioning in the nucleus (PMID: 12909615, 18004398). This variant causes a frameshift at codon 523 and is not expected to affect the NLS, but it may affect protein structure and/or stability. Experimental studies have not been performed to test its effect on protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 27, 2019	The CHEK2 c.1696delC variant is classified as VUS (PM2, PP5) Insufficient evidence; rare, but found in last exon with no other PTC variants downstream definitively regarded as pathogenic. Not effect NMD, and not remove NLS, not particularly well conserved region (Homologene) -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 17, 2023	The c.1567delC variant, located in coding exon 14 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1567, causing a translational frameshift with a predicted alternate stop codon (p.R523Vfs*43). This deletion and subsequent frameshift occurs near the 3' terminus of CHEK2 and results in the last 21 amino acids being replaced by alternate amino acid residues and the elongation of the encoded protein by 21 additional amino acids. The altered amino acids are not predicted to disrupt the nuclear localization signal of the protein (Zannini L et al. J Biol Chem. 2003 Oct 24;278(43):42346-51). However, the added amino acids do change the nature of the C-terminal protein from hydrophilic and disordered to hydrophobic (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2021	This variant deletes 1 nucleotide in exon 15 of the CHEK2 gene, creating a frameshift at codon 523, replacing the last 21 amino acids, and extending the length of the encoded protein by 21 additional amino acids. To our knowledge, this variant has not been reported in published functional studies. This variant has been reported in four individuals with unknown phenotype (PMID: 27751358) and has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 13, 2022	- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 09, 2022

Variant summary: CHEK2 c.1567delC (p.Arg523ValfsX43) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 8.6e-06 in 233408 control chromosomes (gnomAD). c.1567delC has been reported in the literature in individuals affected with various cancers, including prostate and breast cancer (e.g. Hu_2018, Leedom_2016, Slavin_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CHEK2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 09, 2023

The CHEK2 c.1567delC variant is predicted to result in a frameshift and premature protein termination (p.Arg523Valfs*43). This variant has been reported in 4 individuals from a multiple breast/ovarian cancer cohort study (Table 1, Leedom et al. 2016. PubMed ID: 27751358). In ClinVar, this variant has interpretations of both likely pathogenic and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/142737/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 11, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2024

Frameshift variant predicted to result in abnormal protein length as the last 21 amino acid(s) are replaced with 42 different amino acid(s); Observed in individuals with a personal and/or family history of ovarian or other cancers undergoing hereditary cancer panel testing (PMID: 27751358, 28888541); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31056428, 28888541, 29922827, 27751358) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Oct 18, 2023

Frameshift variant in the last exon without known additional PTVs classified as Class 4/5. According to the ACMG standard criteria we chose these criteria: PVS1 (supporting pathogenic): Frameshift variant in the last exon without known additional PTVs, PM2 (supporting pathogenic): Not in gnomAD -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782684; hg19: chr22-29083949;