rs587782245

Positions:

• chr22-28724977-CT-C

Variant summary

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

The NM_007194.4(CHEK2):​c.591delA​(p.Val198fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000018 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CHEK2 NM_007194.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 4.12

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 22-28724977-CT-C is Pathogenic according to our data. Variant chr22-28724977-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28724977-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.591delA	p.Val198fs	frameshift_variant, splice_region_variant	4/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.591delA	p.Val198fs	frameshift_variant, splice_region_variant	4/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251334 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135870

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461740 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727186

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: 0.0000207

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151982 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2021	The CHEK2 c.591del (p.Val198Phefs*7) variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast or prostate cancer in the published literature (PMID: 32906215 (2020), 30706980 (2019), 28008555 (2017), 27433846 (2016), 26681312 (2015), 26022348 (2015)). The frequency of this variant in the general population, 0.00004 (1/24946 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 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; Observed in individuals with prostate cancer and breast cancer (Bell et al., 2007; Pritchard et al., 2016; Decker et al., 2017; Pritzlaff et al., 2017; Girard et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 589delA; This variant is associated with the following publications: (PMID: 17721994, 26681312, 27751358, 30303537, 31447099, 27433846, 28008555, 26022348, 28779002, 33803639, 32906215, 32885271, 27806230, 31398194, 34204722, 32805687, 29922827, 28888541, 34687117, 33804961, 30625039, 34308104, 35441217) -

Familial cancer of breast Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change creates a premature translational stop signal (p.Val198Phefs*7) 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 present in population databases (rs587782245, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast cancer (PMID: 17721994, 26681312, 27433846, 28008555). This variant is also known as 589delA. ClinVar contains an entry for this variant (Variation ID: 142114). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	This variant deletes 1 nucleotide in exon 4 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 breast cancer (PMID: 17721994, 26681312, 28008555, 30303537) and prostate cancer (PMID: 27433846). This variant has been identified in 6/282716 chromosomes 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 2024	The c.591delA pathogenic mutation, located in coding exon 3 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 591, causing a translational frameshift with a predicted alternate stop codon (p.V198Ffs*7). This alteration (designated as 589delA) has been reported in an early-onset breast cancer patient and results in inactivation of CHK2 kinase activity (Bell D et al. Int. J. Cancer. 2007 Dec;121(12):2661-7). It has also been reported in a patient with male breast cancer in his sixties (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). 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. -

CHEK2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The CHEK2 c.591delA variant is predicted to result in a frameshift and premature protein termination (p.Val198Phefs*7). This variant has been reported to be causative for breast cancer (Schroeder et al. 2015. PubMed ID: 26022348, suppl. Table 1) and for metastatic prostate cancer (Pritchard et al. 2016. PubMed ID: 27433846, Table S1). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142114/). Frameshift variants in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 14, 2023

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CHEK2 p.Val198Phefs*7 variant was identified in 4 of 23674 proband chromosomes (frequency: 0.0002) from individuals or families with breast or prostate cancer (Bell 2007, Pritchard 2016, Pritzaff 2016, Susswein 2016). The variant was also identified in dbSNP (ID: rs587782245) as "With Pathogenic allele ", and in ClinVar (classified as pathogenic by Ambry Genetics, GeneDx, Invitae, Color Genomics; as likely pathogenic by Counsil and one clinical laboratory). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.591del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 198 and leads to a premature stop codon at position 204. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease in CHEK2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as 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

Mar 24, 2020

Variant summary: CHEK2 c.591delA (p.Val198PhefsX7) 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 allele was found at a frequency of 2e-05 in 251334 control chromosomes (gnomAD). c.591delA has been reported in the literature in multiple individuals affected with breast cancer (Bell_2007, Schroeder_2015, Susswein_2016, Girard_2019), male breast cancer (Pritzlaff_2017) and prostate cancer (Pritchard_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and noted that a complete loss-of-function may be presumed for this truncating mutation (Bell_2007). Seven 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 (6x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Nov 02, 2021

PVS1, PS3, PM2 -

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: rs587782245; hg19: chr22-29120965;