22-28725027-C-T

Variant names:

• chr22-28725027-C-T
• rs121908701
• NM_007194.4:c.542G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_007194.4(CHEK2):​c.542G>A​(p.Arg181His) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,613,934 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. R181C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (1 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:9 O:1
• Conservation: PhyloP100: 3.74
• Publications: 29 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07827735).
• BP6: Variant 22-28725027-C-T is Benign according to our data. Variant chr22-28725027-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5598.
• BS2: High AC in GnomAd4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.542G>A	p.Arg181His	missense	Exon 4 of 15	NP_009125.1
	CHEK2	NM_001005735.3		c.671G>A	p.Arg224His	missense	Exon 5 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.635G>A	p.Arg212His	missense	Exon 5 of 16	NP_001425222.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.542G>A	p.Arg181His	missense	Exon 4 of 15	ENSP00000385747.1
	CHEK2	ENST00000382580.6	TSL:1	c.671G>A	p.Arg224His	missense	Exon 5 of 16	ENSP00000372023.2
	CHEK2	ENST00000416671.5	TSL:1	n.542G>A		non_coding_transcript_exon	Exon 4 of 16	ENSP00000402225.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251408 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461764 Hom.: 1 Cov.: 32 AF XY: 0.0000660 AC XY: 48 AN XY: 727186

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39682

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111916

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74386

African (AFR) AF: 0.0000722 AC: 3 AN: 41534

American (AMR) AF: 0.000131 AC: 2 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000905 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:5

Apr 28, 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.

Jul 18, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 181 of the CHEK2 protein (p.Arg181His). This variant is present in population databases (rs121908701, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with thyroid cancer, prostate cancer, neuroblastoma, breast cancer, Hodgkin lymphoma, and non-Hodgkin lymphoma (PMID: 12533788, 15095295, 21744992, 23334666, 26506619, 30826992). ClinVar contains an entry for this variant (Variation ID: 5598). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065, 31050813, 34903604). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Mar 09, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

not provided Uncertain:1 Benign:2 Other:1

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 20, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 10, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 29700634, 31118792, 21744992, 15095295, 12533788, 23334666, 26506619, 28055978, 27720647, 28418444, 16982735, 22419737, 30067863, 21059199, 16835864, 29752822, 28580595, 30851065, 31050813, 30287823, 29520813, 31056747, 32906215)

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Feb 17, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 25, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Sep 30, 2022

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.

CHEK2-related cancer predisposition Uncertain:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

May 28, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

not specified Benign:2

Oct 30, 2023

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.542G>A (p.Arg181His) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 360012 control chromosomes (gnomAD and jMorp (Tadaka_2021) databases), predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.542G>A has been reported in the literature in Japanese case control studies of individuals with breast cancer or colorectal cancer with no reported association (e.g., Momozawa_2018, Fujita_2022), as well as in individuals affected with Hodgkins lymphoma, Non-Hodgkins lymphoma, sporadic prostate cancer, or Neuroblastoma, and at-least one individual with breast cancer from a family testing negative for mutations in BRCA1 and 2 genes (e.g., Havranek_2011, Havranek_2015, Dong_2003, Pugh_2013, Dufault_2004). These reports do not provide unequivocal conclusions about the association of this variant with any of these cancers and some even cite this in the context of a neutral variant (e.g., Havranek_2011) or a non-significant association (e.g., Dufault_2004). At least three recent publications report experimental evidence evaluating an impact on protein function. The studies showed no damaging effect of this variant using an in-vivo yeast based assay evaluating the ability to repair MMS (methylmethanesulfonate) induced DNA damage (e.g., Delimitsou_2019) and cell-based assays quantifying KAP1-S473 phosphorylation (e.g., Kleibova_2019, Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35643632, 30851065, 33309985, 21744992, 31050813, 30287823, 23334666, 33179747). Multiple ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments (VUS, n = 11; likely benign, n = 4). Some of these submitters list overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Prostate cancer Uncertain:1

Feb 01, 2003

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Familial cancer of breast;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Uncertain:1

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.Arg181His variant was identified in 4 of 3908 proband chromosomes (frequency: 0.001) from individuals with non-hodgkins lymphoma, neuroblastoma, breast and prostate cancer and was not identified in 2736 control chromosomes from healthy individuals (Dong 2003,Pugh 2013, Dufault 2004, Havranek 2015). The variant was identified in dbSNP (rs121908701) as “with pathogenic allele”, in ClinVar (interpreted as "uncertain significance" by Invitae, Color and 6 others, "pathogenic" by OMIM and not provided 1 other). The variant was identified in control databases in 34 of 277,176 chromosomes (1 homozygous) at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,026 chromosomes (freq: 0.00004), Latino in 1 of 34,420 chromosomes (freq: 0.00003), European in 3 of 126,676 chromosomes (freq: 0.00002), East Asian in 25 of 18,864 chromosomes (freq: 0.001), and South Asian in 4 of 30,782 chromosomes (freq: 0.0001). The variant was not observed in the Other, Ashkenazi Jewish and Finnish, populations. The variant is located within the Forkhead Associate Domain, but further studies are required to determine if it affects protein function. The p.Arg181His residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.

Hereditary breast ovarian cancer syndrome Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Breast and/or ovarian cancer Benign:1

Nov 23, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1

Dipartimento Di Medicina Di Precisione, Università Degli Studi Della Campania Luigi Vanvitelli

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.542G>A (p.Arg181His) in CHEK2, located in exon 4, results in the substitution of arginine with histidine. Initially classified as a Variant of Uncertain Significance (VUS), this variant has been reclassified as benign based on in silico prediction tools indicating a likely tolerated impact on protein function.

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition Benign:1

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.46
Sift	Benign	0.57	T
Sift4G	Benign	0.59	T
Polyphen		0.0080	B
Vest4		0.48
MVP		0.84
MPC		0.022
ClinPred		0.031	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.41
Mutation Taster		=38/62	disease causing

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: rs121908701; hg19: chr22-29121015; COSMIC: COSV100101646; COSMIC: COSV100101646;