rs587780174

Variant names:

• chr22-28695238-TA-T
• rs587780174
• NM_007194.4:c.1263delT

Variant summary

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

The NM_007194.4(CHEK2):​c.1263delT​(p.Ser422ValfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 152,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27 O:2
• Conservation: PhyloP100: -0.387

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 22-28695238-TA-T is Pathogenic according to our data. Variant chr22-28695238-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1263delT	p.Ser422ValfsTer15	frameshift_variant	Exon 12 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1263delT	p.Ser422ValfsTer15	frameshift_variant	Exon 12 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250264 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135312

Gnomad AFR exome AF: 0.0000622

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: 0.0000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000247 AC: 346 AN: 1403334 Hom.: 2 Cov.: 24 AF XY: 0.000237 AC XY: 166 AN XY: 701402

Gnomad4 AFR exome AF: 0.0000311

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: 0.000321

Gnomad4 OTH exome AF: 0.0000855

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:27 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:7

Dec 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 12 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, bladder, colon, hematological, prostate and urethral cancer (PMID: 21244692, 24556621, 26534844, 26681312, 27273131, 33803639). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 25/60466 cases and 5/53461 unaffected controls (OR=4.422 (95%CI 1.693 to 11.552)) (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000325). This variant has been identified in 13/281654 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. -

Jan 12, 2018

True Health Diagnostics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 07, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2018

Academic Department of Medical Genetics, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Aug 08, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1263delT pathogenic mutation, located in coding exon 11 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1263, causing a translational frameshift with a predicted alternate stop codon (p.S422Vfs*15). This mutation has been reported in individuals with multiple cancer types including female breast, male breast, prostate, urethral, bladder, renal, pancreatic, colon, and sarcoma (Le Calvez-Kelm F et al. Breast Cancer Res, 2011 Jan;13:R6; Leongamornlert D et al. Br. J. Cancer, 2014 Mar;110:1663-72; Mauer CB et al. Genet. Med., 2014 May;16:407-12; Byers H et al. Eur J Hum Genet, 2016 11;24:1591-1597; Susswein LR et al. Genet Med, 2016 08;18:823-32; Leedom TP et al. Cancer Genet, 2016 09;209:403-407; AlDubayan SH et al. JAMA Oncol, 2019 Apr;5:514-522; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Smith PS et al. Genes Chromosomes Cancer, 2021 01;60:5-16; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this variant was reported in 25/60,466 breast cancer cases as well as 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. -

Dec 09, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift deletion NM_001005735.2(CHEK2):c.1392delT (p.Ser465Valfs*15) has been reported to ClinVar as Pathogenic/Likely pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 128053 as of 2024-11-07). The p.Ser465Valfs*15 variant is observed in 10/113,048 (0.0088%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. This indicates that the region is critical to protein function. The p.Ser465Valfs*15 variant is a loss of function variant in the gene CHEK2, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_001005735.1:p.R3Vfs*4 and 668 others. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:6

Jun 18, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 a significant frequency in large population cohorts (Lek 2016); Also known as c.1392delT (p.Ser465ValfsX15); This variant is associated with the following publications: (PMID: 25431674, 24113346, 28779002, 29961768, 29625052, 21244692, 26681312, 24556621, 27273131, 27751358, 26787654, 28152038, 26534844, 29287968, 29520813, 29909963, 24763289, 30676620, 31263054, 31447099, 32832836) -

Feb 10, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 27273131 (2016), 26534844 (2016), 21244692 (2011)) and prostate cancer (PMID: 24556621 (2014)). Based on the available information, this variant is classified as pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 p.Ser422ValfsX15 variant was identified in 22 of 115016 proband chromosomes (frequency: 0.0002) from individuals or families with breast, prostate, and other types of cancer (Byers 2016, Calvez-Kelm 2011, Leedom 2016, Leongamornlert 2014, Mauer 2014, Susswein 2016). The variant was also identified in the following databases: dbSNP (ID: rs587780174) as "With Pathogenic allele", ClinVar (4x pathogenic), and Clinvitae (3x pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was also not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In a study by Leongamornlert (2014), this variant was found to segregate with 2 of 3 affected family members with prostate cancer. The c.1263delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 422 and leads to a premature stop codon 15 codons downstream. 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 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. -

Apr 28, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the CHEK2 gene demonstrated a one base pair deletion in exon 12, c.1263del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon fourteen amino acids downstream of the mutation, p.Ser422Valfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in patients with CHEK2-related cancers (PMIDs: 21244692, 24113346, 24556621, 26681312). -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHEK2: PVS1, PS4:Moderate -

Familial cancer of breast Pathogenic:6

Nov 26, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser422Valfs*15) 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 (rs587780174, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast, prostate, bladder, colon and urethral cancer (PMID: 21244692, 24113346, 24556621, 26681312). ClinVar contains an entry for this variant (Variation ID: 128053). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Jul 05, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS4_STR -

Li-Fraumeni syndrome 2 Pathogenic:1 Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 04-28-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Apr 28, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4 -

CHEK2-related cancer predisposition Pathogenic:1 Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 10-21-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Nov 01, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.1263delT (p.Ser422ValfsTer15) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser422ValfsTer15 variant has been reported in at least six studies in at least 25 individuals undergoing hereditary cancer testing or diagnosed with various cancer types (La Calvez-Kelm et al. 2011; Leongamornlert et al. 2014; Mauer et al. 2014; Susswein et al. 2015; Byers et al. 2016; Leedom et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of frameshift variants, the p.Ser422ValfsTer15 variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

CHEK2-related disorder Pathogenic:1

Jul 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 c.1263delT variant is predicted to result in a frameshift and premature protein termination (p.Ser422Valfs*15). This variant has been reported in multiple individuals with CHEK2-related cancers (Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Leongamornlert et al. 2014. PubMed ID: 24556621; Susswein et al. 2016. PubMed ID: 26681312; Decker et al. 2017. PubMed ID: 28779002; Whitworth et al 2018. PubMed ID: 29909963; Yurgelun et al 2019. PubMed ID: 29961768). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12805). Frameshift variants in CHEK2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Feb 28, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of prostate Pathogenic:1

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Predisposition to cancer Pathogenic:1

May 05, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.1263del (p.Ser422ValfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been reported in individuals with breast, colon, prostate, bladder, and urethral cancer (PS4; PMID: 21244692, 24556621, 26534844, 26681312, 27273131, 33803639). This variant has a maximum subpopulation frequency of 0.0086% in gnomAD v2.1.1 (https:// gnomad.broadinstitute.org/). Other truncating variants in exon 12 have been reported in individuals with CHEK2-associated cancers and are known to be pathogenic (PM5_supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM5_supporting. -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Jan 26, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CHEK2 c.1263delT (p.Ser422Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent CHEK2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate protein kinase domain. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory and others (e.g. p.Arg519X, c.1434delA, etc.). This variant was found in 6/117456 control chromosomes at a frequency of 0.0000511, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). This variant has been reported in multiple cancer patients including breast and prostate cancer and is classified as pathogenic in literature and by multiple clinical diagnostic laboratories/reputable databases. Taken together, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780174; hg19: chr22-29091226;