22-28734664-G-A

Variant names:

• chr22-28734664-G-A
• rs536907995
• NM_007194.4:c.58C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_007194.4(CHEK2):​c.58C>T​(p.Gln20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: CHEK2 NM_007194.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20 U:1 O:1
• Conservation: PhyloP100: 2.29

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 36 pathogenic variants in the truncated region.
• PP5: Variant 22-28734664-G-A is Pathogenic according to our data. Variant chr22-28734664-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133887.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=10, Likely_pathogenic=4, not_provided=1}. Variant chr22-28734664-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.58C>T	p.Gln20*	stop_gained	Exon 2 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.58C>T	p.Gln20*	stop_gained	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 31

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: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000141 AC: 35 AN: 247462 Hom.: 0 AF XY: 0.000201 AC XY: 27 AN XY: 134030

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.0000935 AC XY: 68 AN XY: 727180

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: 0.00111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:20 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:7

Jan 17, 2023

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 termination codon and is predicted to result in premature protein truncation. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A pathogenic mutation was detected in the CHEK2 gene (c.58C>T).This sequence change creates a premature translational stop signal (p.Gln20*) in the CHEK2 gene. This variant is expected to result in an absent or non-functional protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant Not observed at a significant frequency in large population cohorts (gnomAD). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887) classified as pathogenic with no conflict . For these reasons, this variant has been classified as Pathogenic. -

Jun 05, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 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.Gln20*) 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 (rs536907995, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 26023681, 27039729, 27510020, 28724667). ClinVar contains an entry for this variant (Variation ID: 133887). For these reasons, this variant has been classified as Pathogenic. -

Oct 26, 2023

Biotechnology, Institute of Science, Nirma University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 constitutional genetic variant leads to a premature truncation of the protein at 20 amino acids leading to loss of the domains crucial for the interaction of proteins like ATM/BRCA2 which are master regulator of the DNA damage repair pathways. The outcome of this mutation could be observed in various cancers specially breast and ovarian cancers, which also corroborates with the familial breast cancer history of the proband, although the proband is yet asymptomatic. Hence, keeping in view the functional effect the variant has been classified pathogenic. -

not provided Pathogenic:6

Mar 08, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 26, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant is predicted to cause the premature termination of CHEK2 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMIDs: 26023681 (2015), 27510020 (2016), 28724667 (2017), 32658311 (2021), and 32885271 (2021)). Based on the available information, this variant is classified as likely pathogenic. -

Feb 03, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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 (gnomAD); Observed in individuals with a personal or family history of CHEK2-related cancers in published literature (Foley 2015, Baloch 2016, Scarpa 2017, Sun 2017, Fan 2018, Akcay 2020); This variant is associated with the following publications: (PMID: 26023681, 28724667, 28199314, 27039729, 24728327, 27510020, 29356917, 28779002, 29922827, 28553140, 32658311) -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Nov 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 2 of the CHEK2 gene, creating a 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: 27039729, 28724667, 32658311, 32885271), an individual affected with ovarian cancer (PMID: 32885271) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000005). This variant has also been observed in an individual affected with breast and ovarian cancer, who carried a pathogenic variant in the BRCA2 gene (PMID: 26023681). This variant is found at a high frequency in the South Asian population (0.1145%, 35/30544 chromosomes) by the Genome Aggregation Database (gnomAD), suggesting its penetrance may be reduced relative to other pathogenic CHEK2 alleles. Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic -

Dec 21, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 18, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q20* pathogenic mutation (also known as c.58C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 58. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration was detected in conjunction with a pathogenic BRCA2 mutation in an individual diagnosed with breast cancer at ages 37 and 61 and ovarian cancer at age 56 (Foley SB et al. EBioMedicine. 2015 Jan;2:74-81). This alteration has also been observed in breast cancer cohorts (Baloch AH et al. Asian Pac. J. Cancer Prev. 2016;17:1089-92; Sun J et al. Clin Cancer Res 2017 Oct;23(20):6113-6119). In one case-control study, this alteration was not identified in 13087 breast cancer cases but was seen in 1/5488 control individuals in the United Kingdom; of note, study subjects were under the age of 55 years (Decker B et al. J Med Genet 2017 11;54(11):732-741). 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. -

Li-Fraumeni syndrome 2 Pathogenic:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast;C0585442:Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2+PS4_Supporting+PVS1 -

Familial ovarian cancer Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 p.Gln20* variant was identified in 2 of 858 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Baloch 2016, Foley 2014). The variant was also identified in dbSNP (ID: rs536907995) as "With Pathogenic allele", and in ClinVar (classified as likely pathogenic by GeneDx, Color Genomics; as pathogenic by Invitae, Counsyl). The variant was not identified in the Zhejiang University database. The variant was identified in control databases in 36 of 242162 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the South Asian population in 36 of 30708 chromosomes (freq: 0.001); it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The c.58C>T variant leads to a premature stop codon at position 20 which is predicted to lead to 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Breast carcinoma Pathogenic:1

Sep 12, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inherited breast cancer and ovarian cancer Uncertain:1

Apr 24, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.72
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs536907995; hg19: chr22-29130652;