22-28734470-T-C

Position:

• chr22-28734470-T-C

Variant summary

Our verdict is Benign. Variant got -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:19
• Conservation: PhyloP100: 0.284

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 142139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28734470-T-C is described in Lovd as [Benign]. Variant chr22-28734470-T-C is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.252A>G	p.Glu84Glu	synonymous_variant	2/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.252A>G	p.Glu84Glu	synonymous_variant	2/15	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

GnomAD3 exomes AF: 0.0355 AC: 8931 AN: 251438 Hom.: 255 AF XY: 0.0351 AC XY: 4773 AN XY: 135898

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 SAS exome AF: 0.0388

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

Gnomad4 AFR exome AF: 0.0693

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0842

Gnomad4 EAS exome AF: 0.0527

Gnomad4 SAS exome AF: 0.0383

Gnomad4 FIN exome AF: 0.0272

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0388

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

Gnomad4 AFR AF: 0.0649

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.0892

Gnomad4 EAS AF: 0.0781

Gnomad4 SAS AF: 0.0350

Gnomad4 FIN AF: 0.0255

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0300 Hom.: 120

Bravo AF: 0.0403

EpiCase AF: 0.0254

EpiControl AF: 0.0251

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial cancer of breast Benign:4

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 05, 2018	- -

CHEK2-related cancer predisposition Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.70

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