22-28734470-T-C

Variant names:

• chr22-28734470-T-C
• rs1805129
• NM_007194.4:c.252A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007194.4(CHEK2):​c.252A>G​(p.Glu84Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,612,750 control chromosomes in the GnomAD database, including 1,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (164 hom., cov: 31)
  • Exomes 𝑓: 0.029 (865 hom.)
• Consequence: CHEK2 NM_007194.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.284
• Publications: 25 publications found

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]

CHEK2 Gene-Disease associations (from GenCC):

• CHEK2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 22-28734470-T-C is Benign according to our data. Variant chr22-28734470-T-C is described in ClinVar as Benign. ClinVar VariationId is 142139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.284 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.252A>G	p.Glu84Glu	synonymous_variant	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.252A>G	p.Glu84Glu	synonymous_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5939 AN: 151196 Hom.: 164 Cov.: 31

Gnomad AFR AF: 0.0646

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0892

Gnomad EAS AF: 0.0789

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0355 AC: 8931 AN: 251438 AF XY: 0.0351

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0852

Gnomad EAS exome AF: 0.0898

Gnomad FIN exome AF: 0.0289

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0289 AC: 42275 AN: 1461438 Hom.: 865 Cov.: 33 AF XY: 0.0294 AC XY: 21358 AN XY: 727054

African (AFR) AF: 0.0693 AC: 2321 AN: 33474

American (AMR) AF: 0.0127 AC: 569 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 2198 AN: 26110

East Asian (EAS) AF: 0.0527 AC: 2090 AN: 39688

South Asian (SAS) AF: 0.0383 AC: 3300 AN: 86212

European-Finnish (FIN) AF: 0.0272 AC: 1455 AN: 53396

Middle Eastern (MID) AF: 0.0427 AC: 246 AN: 5764

European-Non Finnish (NFE) AF: 0.0250 AC: 27756 AN: 1111706

Other (OTH) AF: 0.0388 AC: 2340 AN: 60372

GnomAD4 genome AF: 0.0393 AC: 5949 AN: 151312 Hom.: 164 Cov.: 31 AF XY: 0.0392 AC XY: 2895 AN XY: 73922

African (AFR) AF: 0.0649 AC: 2673 AN: 41214

American (AMR) AF: 0.0213 AC: 324 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0892 AC: 309 AN: 3464

East Asian (EAS) AF: 0.0781 AC: 400 AN: 5120

South Asian (SAS) AF: 0.0350 AC: 167 AN: 4768

European-Finnish (FIN) AF: 0.0255 AC: 268 AN: 10518

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1724 AN: 67736

Other (OTH) AF: 0.0312 AC: 65 AN: 2084

Alfa AF: 0.0307 Hom.: 171

Bravo AF: 0.0403

EpiCase AF: 0.0254

EpiControl AF: 0.0251

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2016

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 09, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CHEK2-related cancer predisposition Benign:2

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 p.Glu84Glu variant was identified in 80 of 2744 proband chromosomes (frequency: 0.03) from families with high risk of HBOC and/or Li-Fraumeni-like syndromes and was present in 43 of 1644 control chromosomes (frequency: 0.03) from healthy individuals (Ingvarsson 2002, Mohamad 2015, Novak 2008, Rashid 2013, Ruijs 2009, Sodha 2002, Staalesen 2004, Kilpivaara 2004, Bayasal 2004). In one study the variant co-occurred with a BRCA2 pathogenic variant (Ingvarsson 2002). The variant was also identified in dbSNP (ID: rs1805129) as “With Likely benign” allele, ClinVar (classified as benign by Ambry Genetics, Prevention Genetics, Counsyl, Color Genomics and Invitae; and likely benign by Illumina), Clinvitae (3x benign and 2x likely benign), Zhejiang Colon Cancer Database (7x) and was not identified in Cosmic database. The variant was identified in control databases in 9839 (265 homozygous) of 276942 chromosomes at a frequency of 0.04 (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: East Asian in 1688 of 18848 chromosomes (freq: 0.09), Ashkenazi Jewish* in 864 of 10150 chromosomes (freq: 0.085), African in 1565 of 23956 chromosomes (freq: 0.065), South Asian in 1209 of 30778 chromosomes (freq: 0.039), Other in 201 of 6450 chromosomes (freq: 0.031), European (Finnish) in 733 of 25778 chromosomes (freq: 0.028), European (Non-Finnish) in 3152 of 126566 chromosomes (freq: 0.025), Latino in 427 of 34416 chromosomes (freq: 0.012) increasing the likelihood this could be a low frequency benign variant. The p.Glu84Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.70
PhyloP100		0.28
PromoterAI		-0.021	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805129; hg19: chr22-29130458; COSMIC: COSV60417575; COSMIC: COSV60417575;