rs137853010

chr22-28725028-G-Achr22-28725028-G-Cchr22-28725028-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007194.4(CHEK2):c.541C>T(p.Arg181Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000806 in 1,613,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:18
• Conservation: PhyloP100: 2.67

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16097897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.541C>T	p.Arg181Cys	missense_variant	4/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.541C>T	p.Arg181Cys	missense_variant	4/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151874 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251404 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135890

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000828 AC: 121 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151874 Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6 AN XY: 74146

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000616 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 181 of the CHEK2 protein (p.Arg181Cys). This variant is present in population databases (rs137853010, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with CHEK2-related conditions (PMID: 18058223, 18996005, 22419737, 29522266, 36468172). ClinVar contains an entry for this variant (Variation ID: 5597). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 16835864, 22419737, 30851065). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 29, 2023	a variant of uncertain significance was detected in the CHEK2 gene (c.541C>T). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 181 of the CHEK2 protein (p.Arg181Cys).This amino acid position is poorly conserved(PhyloP=2.3). This variant is present in population databases (rs137853010, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast, ovarian and colorectal cancer (PMID: 18058223, 18996005, 22419737, 29522266). ClinVar contains an entry for this variant (Variation ID: 5597). In addition, this alteration is predicted to be tolerated by in silico analysis. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2016	- -

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2023	Observed in individuals with CHEK2-related cancers, but also in unaffected controls (Dong et al., 2003; Wu et al., 2006; Zheng et al., 2006; Kleibl et al., 2008; Kleibl et al., 2009; Decker et al., 2017; Hauke et al., 2018; Momozawa et al., 2018; Wu et al., 2018; Greville-Heygate et al., 2020; Dorling et al., 2021; Wallander et al., 2021); Published functional studies are conflicting: some show reduced response to DNA damage and kinase activity, while others show kinase activity and DNA damage response comparable to wild-type (Wu et al., 2006; Roeb et al., 2012; Delimitsou et al., 2019; Kleiblova et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26822949, 16835864, 27157322, 12533788, 22419737, 18058223, 16941491, 18996005, 19782031, 21765476, 29520813, 28873162, 30851065, 31050813, 30287823, 34711244, 34426522, 36468172, 28125078, 28779002, 26580448, 29522266, 32923877, 33471991) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 08, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2022	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.541C>T, in exon 4 that results in an amino acid change, p.Arg181Cys. This sequence change has been previously described in one individual with prostate cancer (PMID: 29520813) and has been described in the gnomAD database with a frequency of 0.011% in the overall population (dbSNP rs137853010). The p.Arg181Cys change affects a poorly conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg181Cys substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg181Cys change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2022	Variant summary: CHEK2 c.541C>T (p.Arg181Cys) 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 0.00011 in 251404 control chromosomes, predominantly at a frequency of 0.00052 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant might be a benign polymorphism. c.541C>T has been reported in the literature in individuals affected with prostate-, breast- and colorectal cancer, as well as in pediatric acute lymphoblastic leukemia and Ewing sarcoma, and multiple primary tumors (Dong_2003, Wu_2018, Kleibl_2008, Kleibl_2009, Zhang_2016, Brohl_2017, Dorling_2021, Wallander_2021), however it was also reported in several unaffected controls (Momozawa_2018, Kleiblova_2019, Narang_2020, Dorling_2021, Mizukami_2020). These reports therefore do not provide unequivocal conclusions about association of the variant with the disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated for the variant protein unaffected autophosphorylation, but partially reduced kinase activity in a mammalian cell system (Wu_2006), as well as an intermediate response to DNA damage in a yeast complementation assay (Roeb_2012). However later studies reported the variant to be similar to WT in a yeast complementation assay (Delimitsou_2019) and with unaffected kinase activity in mammalian cells (Kleiblova_2019). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 21, 2022	The p.R181C variant (also known as c.541C>T), located in coding exon 3 of the CHEK2 gene, results from a C to T substitution at nucleotide position 541. The arginine at codon 181 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in breast cancer, colorectal cancer, and prostate cancer patients (Zheng L et al. Hum. Mutat. 2006 Oct;27:1062-3; Wu Y et al. Prostate. 2018 Jun;78:607-615; Kleibl Z et al. Breast Cancer Res. Treat. 2008 Nov;112:159-64; Hauke J et al. Cancer Med. 2018 Apr;7:1349-1358; Kleibl Z et al. Eur. J. Cancer. 2009 Mar;45:618-24). It has also been reported in pediatric cancer patients and patients with advanced cancer (Zhang J et al. N. Engl. J. Med. 2015 Dec;373:2336-2346; Mandelker D et al. JAMA. 2017 09;318:825-835). Functional studies have shown that this alteration results in partially reduced Chk2 kinase activity and, in a yeast-based assay to assess in vivo Chk2-mediated response to cell damage, this alteration showed an intermediate response (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2023	This missense variant replaces arginine with cysteine at codon 181 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown conflicting results, showing the mutant protein to be functional (PMID: 16835864, 30851065, 31050813), exhibit partially reduced activity (PMID: 22419737), or no activity (PMID: 36468172). This variant has been reported in individuals affected with breast cancer (PMID: 18058223, 22419737, 29522266, 34711244), colorectal cancer (PMID: 18996005, 34711244), prostate cancer (PMID: 12533788, 16835864, 29520813), and other hereditary cancers (PMID: 26580448, 28873162, 36468172). In a large breast cancer case-control study, this variant has been observed in 6/60466 cases and 3/53461 unaffected controls (OR=1.768, 95%CI 0.442 to 7.071; p-value=0.515; Leiden Open Variation Database DB-ID CHEK2_000021)(PMID: 33471991). This variant has been observed together with pathogenic BRCA1 and BRCA2 variants in individuals affected with breast cancer (Color internal data). This variant has been identified in 31/282774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 08, 2021	- -

Prostate cancer, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	23
Dann	Uncertain	0.97
DEOGEN2	Benign	0.36	T;.;T;T;.;T;.;.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L;L;L;L;.;L;L;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;N;N;N;N;.;N;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.20	T;T;T;T;T;.;T;T;.
Sift4G	Benign	0.20	T;T;T;T;T;.;T;T;T
Polyphen		0.0020	B;B;B;B;B;B;B;.;.
Vest4		0.44
MVP		0.92
MPC		0.022
ClinPred		0.026	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.28
gMVP		0.49

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: rs137853010; hg19: chr22-29121016; COSMIC: COSV60428467; COSMIC: COSV60428467;