rs145754558

Variant names:

• chr22-28719499-G-A
• rs145754558
• NM_007194.4:c.593-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28719499-G-A
• chr22-28719499-G-C
• chr22-28719499-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007194.4(CHEK2):​c.593-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,457,612 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (21 hom.)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.235
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-28719499-G-A is Benign according to our data. Variant chr22-28719499-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0014 (1825/1305342) while in subpopulation EAS AF = 0.0101 (386/38162). AF 95% confidence interval is 0.00928. There are 21 homozygotes in GnomAdExome4. There are 893 alleles in the male GnomAdExome4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.593-14C>T		intron_variant	Intron 4 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.593-14C>T		intron_variant	Intron 4 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00904

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00312 AC: 612 AN: 195858 AF XY: 0.00294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000347

Gnomad ASJ exome AF: 0.00257

Gnomad EAS exome AF: 0.00802

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00140 AC: 1825 AN: 1305342 Hom.: 21 Cov.: 20 AF XY: 0.00137 AC XY: 893 AN XY: 653132

African (AFR) AF: 0.00 AC: 0 AN: 30338

American (AMR) AF: 0.0000502 AC: 2 AN: 39860

Ashkenazi Jewish (ASJ) AF: 0.00228 AC: 56 AN: 24594

East Asian (EAS) AF: 0.0101 AC: 386 AN: 38162

South Asian (SAS) AF: 0.000252 AC: 20 AN: 79412

European-Finnish (FIN) AF: 0.0194 AC: 989 AN: 50928

Middle Eastern (MID) AF: 0.000187 AC: 1 AN: 5358

European-Non Finnish (NFE) AF: 0.000294 AC: 289 AN: 981876

Other (OTH) AF: 0.00150 AC: 82 AN: 54814

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00906 AC: 47 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0202 AC: 214 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.00839 AC: 29 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 16, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 13, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Feb 09, 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. -

Hereditary cancer-predisposing syndrome Benign:3

Feb 03, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4 c.593-14C>T is an intronic variant located close to a canonical splice site. The variant allele was found in 130/16644 alleles, with a filter allele frequency of 0.63% at 99% confidence in the gnomAD v2.1.1 database (East Asian)(BS1). The SpliceAI algorithm predicts no significant impact on splicing (BP4). To our knowledge, neither clinical data nor functional studies have been reported for this variant It has been identified in the following databases, ClinVar (10x benign, 3x likely benign) and LOVD (4x benign). Based on currently available information, the variant c.593-14C>T is classified as a likely benign variant according to ACMG guidelines. -

Jun 30, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Aug 26, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 c.593-14C>T variant was not identified in the literature nor was it identified in the Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs145754558) as “With Likely benign allele”, ClinVar (as benign by GeneDx, Counsyl), Clinvitae (as benign by ClinVar), databases. The variant was identified in control databases in 752 of 221734 (8 homozygous) chromosomes at a frequency of 0.003 in the following populations: other in 22 of 5482 chromosomes (freq. 0.004), Latino in 1 of 28996 chromosomes (freq. 0.000034), European in 114 of 93630 (1 homozygous) chromosomes (freq. 0.0012), Ashkenazi Jewish in 22 of 9042 chromosomes (freq. 0.0024), East Asian in 128 of 16184 (1 homozygous) chromosomes (freq. 0.008), Finnish in 460 of 22300 (6 homozygous) chromosomes (freq. 0.02),and South Asian in 5 of 25738 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely 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

- -

CHEK2-related cancer predisposition Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

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: rs145754558; hg19: chr22-29115487;