22-28689188-C-T

Variant names:

• chr22-28689188-C-T
• rs143965148
• NM_007194.4:c.1489G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_007194.4(CHEK2):​c.1489G>A​(p.Asp497Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,593,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D497G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10
• Conservation: PhyloP100: -0.245
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014125377).
• BP6: Variant 22-28689188-C-T is Benign according to our data. Variant chr22-28689188-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142445.
• BS2: High AC in GnomAd4 at 22 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1489G>A	p.Asp497Asn	missense_variant	Exon 14 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1489G>A	p.Asp497Asn	missense_variant	Exon 14 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000240 AC: 56 AN: 233606 AF XY: 0.000210

Gnomad AFR exome AF: 0.000408

Gnomad AMR exome AF: 0.000902

Gnomad ASJ exome AF: 0.000507

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000460

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.000112 AC: 162 AN: 1441576 Hom.: 0 Cov.: 29 AF XY: 0.000100 AC XY: 72 AN XY: 717722

African (AFR) AF: 0.000210 AC: 7 AN: 33342

American (AMR) AF: 0.000984 AC: 44 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38012

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4128

European-Non Finnish (NFE) AF: 0.0000685 AC: 76 AN: 1109512

Other (OTH) AF: 0.000233 AC: 14 AN: 60024

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74458

African (AFR) AF: 0.000265 AC: 11 AN: 41556

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.000227 AC: 26

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CHEK2 p.Asp497Asn variant was not identified in the literature nor was it identified in the Cosmic and MutDB. The variant was identified in dbSNP (ID: rs143965148) as “With other allele”, ClinVar (classified as likely benign by Ambry Genetics, Invitae and Laboratory Corporation of America, and uncertain significance by GeneDx and Counsyl), Clinvitae (3x), Zhejiang University Database (1x), and in control databases in 57 of 260048 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 9 of 22562 chromosomes (freq: 0.0004), Other in 5 of 6274 chromosomes (freq: 0.0008), Latino in 32 of 34204 chromosomes (freq: 0.0009), European Non-Finnish in 7 of 121964 chromosomes (freq: 0.00006), Ashkenazi Jewish in 4 of 9954 chromosomes (freq: 0.0004); it was not observed in the East Asian, Finnish, and South Asian populations. The p.Asp497 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact of the variant Asn to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jun 24, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with breast, endometrial, or ovarian cancer, but also in unaffected controls (PMID: 25186627, 27443514, 32546565, 31206626, 33471991, 34326862, 38061684); Published functional studies suggest no damaging effect: normal cell growth after exposure to DNA damage, and KAP1 and CHK2 kinase activity in the wild-type range in vitro (PMID: 30851065, 37449874); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 25186627, 32546565, 31398194, 32906215, 25085752, 37216304, 34326862, 31206626, 33471991, 38061684, 30851065, 37449874, 22419737, 19782031) -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Familial cancer of breast Uncertain:1 Benign:3

Jun 23, 2016

Counsyl

Significance: Uncertain significance

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 08, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely 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]. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jun 09, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHEK2 c.1489G>A (p.Asp497Asn) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 0.00024 in 233606 control chromosomes, predominantly at a frequency of 0.0009 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). This variant has also been reported among women who are cancer free and older than age 70 (FLOSSIES database). c.1489G>A has been observed in individual(s) undergoing clinical genetic testing for breast cancer (example, Tung_2015, Vargas-Parra_2020, Infante_2024), endometrial carcinoma (Ring_2016), and has also been reported in both cancer cohorts and control groups (Weitzel_2019, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Delimitsou_2019, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 33471991, 38061684, 27443514, 37449874, 25186627, 32906215, 31206626). ClinVar contains an entry for this variant (Variation ID: 142445). Based on the evidence outlined above, the variant was classified as likely benign. -

Nov 29, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

May 01, 2019

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. -

Dec 08, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHEK2-related disorder Uncertain:1

Mar 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.1489G>A variant is predicted to result in the amino acid substitution p.Asp497Asn. This variant has been reported in an individual with endometrial cancer who also had other variants of uncertain significance (Ring et al. 2016. PubMed ID: 27443514, Supplemental Table 2, Study ID: 05-212), in an individual with breast cancer (Tung et al. 2015. PubMed ID: 25186627, supporting information 2), and in an individual with undefined hereditary cancer from a large cohort (Vargas-Parra. 2020. PubMed ID: 32906215). This variant is reported in 0.088% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29085176-C-T) and has conflicting interpretations in ClinVar, ranging from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/142445/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Benign:1

Feb 15, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): spliceAI: CHEK2: 0.0, REVEL: 0.036, BS1 (strong benign): gnomAD v2.1.1 FAF Exom >0,05%, BS3 (strong benign): Delimitsou 2018/Stolarova 2023: benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.5
DANN	Benign	0.92
DEOGEN2	Benign	0.081	T;.;T;.;T;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.66	.;T;.;T;.;T;T;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;N;.;N;.;N;.;.
PhyloP100		-0.24
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.53	N;N;N;.;N;N;.;N;N
REVEL	Benign	0.036
Sift	Benign	0.52	T;T;T;.;T;T;.;T;T
Sift4G	Benign	0.40	T;T;T;.;T;T;.;T;T
Polyphen		0.0	B;B;B;.;B;B;B;B;B
Vest4		0.14
MutPred		0.22		Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);.;.;
MVP		0.41
MPC		0.019
ClinPred		0.00098	T
GERP RS		-0.40
Varity_R		0.11
gMVP		0.27
Mutation Taster		=92/8	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: rs143965148; hg19: chr22-29085176;