rs786202601

Positions:

• chr22-28694058-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007194.4(CHEK2):​c.1434del​(p.Glu479LysfsTer3) variant causes a frameshift 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.866

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-28694058-CT-C is Pathogenic according to our data. Variant chr22-28694058-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 185972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1434del	p.Glu479LysfsTer3	frameshift_variant	13/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1434del	p.Glu479LysfsTer3	frameshift_variant	13/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Glu479Lysfs*3) 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 premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 27751358). ClinVar contains an entry for this variant (Variation ID: 185972). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 28, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 21, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2024	The c.1434delA pathogenic mutation, located in coding exon 12 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1434, causing a translational frameshift with a predicted alternate stop codon (p.E479Kfs*3). 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	Jan 15, 2020	This variant deletes 1 nucleotide in exon 13 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 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. -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 18, 2019

Variant summary: CHEK2 c.1434delA (p.Glu479LysfsX3) 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 233796 control chromosomes (gnomAD). The variant, c.1434delA, has been reported in the literature in two individuals who were referred for multi-gene cancer panel testing, but with limited available information (Leedom_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32805687, 27751358, 37490054) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786202601; hg19: chr22-29090046;