rs786202497

Positions:

• chr22-28719422-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000404276.6(CHEK2):​c.655del​(p.Glu219AsnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,441,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E219E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CHEK2 ENST00000404276.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.883

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 22-28719422-TC-T is Pathogenic according to our data. Variant chr22-28719422-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.655del	p.Glu219AsnfsTer16	frameshift_variant	5/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.655del	p.Glu219AsnfsTer16	frameshift_variant	5/15	1	NM_007194.4	ENSP00000385747	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000166 AC: 24 AN: 1441946 Hom.: 0 Cov.: 28 AF XY: 0.0000181 AC XY: 13 AN XY: 716386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000218

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 15, 2021	CHEK2:c.655del is a deletion of a single nucleotide in exon 5 predicted to encode a frameshift of the mature mRNA with consequent premature termination of protein synthesis at codon 16 of the frameshift, or 234 (CHEK2:p.( Glu219AsnfsTer16)) using NP_009125.1. This is predicted to result in absent CHEK2 protein due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic (Tayoun, et al., 2018, PMID:30192042) (PVS1). CHEK2:c.655del (rs786202497) is absent from population databases and is not on record in the control database FLOSSIES (PM2). This variant has been detected in one individual with colorectal polyps and parathyroid cancer, and one individual with prostate cancer (Whitworth et al., 2018, PMID:29909963; Nguyen-Dumont et al., 2020, PMID:32338768). This variant has not been reported in the scientific literature in association with breast cancer. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change creates a premature translational stop signal (p.Glu219Asnfs*16) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185842). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 26, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 10, 2023	The c.655delG pathogenic mutation, located in coding exon 4 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 655, causing a translational frameshift with a predicted alternate stop codon (p.E219Nfs*16). This alteration, designated as NM_001005735 c.784delG, has been reported in a cohort of 460 individuals from 440 families with at least two primary tumors by age 60 years or at least three by 70 years (Whitworth J et al. Am J Hum Genet, 2018 07;103:3-18). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2021	This variant deletes 1 nucleotide in exon 5 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with multiple primary tumor (PMID: 29909963) and prostate cancer (PMID: 32338768). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

Breast and/or ovarian cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 07, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2017

This deletion of one nucleotide in CHEK2 is denoted c.655delG at the cDNA level and p.Glu219AsnfsX16 (E219NfsX16) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGAT[delG]AATA. The deletion causes a frameshift which changes a Glutamic Acid to an Asparagine at codon 219, and creates a premature stop codon at position 16 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 19, 2019

Variant summary: CHEK2 c.655delG (p.Glu219AsnfsX16) 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 230178 control chromosomes (gnomAD). c.655delG has been reported in the literature in an individual affected with multiple primary tumors (Whitworth_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (3x pathogenic, 1x likely pathogenic). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs786202497; hg19: chr22-29115410;