rs77130927

chr22-28725031-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_007194.4(CHEK2):c.538C>T(p.Arg180Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000828 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R180H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:12
• Conservation: PhyloP100: 4.79

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022102207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.538C>T	p.Arg180Cys	missense_variant	4/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.538C>T	p.Arg180Cys	missense_variant	4/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.000619 AC: 94 AN: 151932 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00560

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000530

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00100 AC: 252 AN: 251406 Hom.: 0 AF XY: 0.00102 AC XY: 139 AN XY: 135896

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00321

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000850 AC: 1243 AN: 1461790 Hom.: 0 Cov.: 32 AF XY: 0.000854 AC XY: 621 AN XY: 727196

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00166

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000890

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000686 AC XY: 51 AN XY: 74310

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00561

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000904 Hom.: 0

Bravo AF: 0.000699

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:4

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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CHEK2 p.Arg180Cys variant was identified in 172 of 93852 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and ovarian cancer, prostate cancer and Lynch syndrome and was present in 147 of 89446 control chromosomes (frequency: 0.002) from healthy individuals (Dong 2003, Dufault 2004, Kleibl 2008, Laitman 2007, Mohamad 2015, Mohelnikova Duchonova 2010, Ng 2016, Southey 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs77130927) as “With other allele”, ClinVar (classified as benign by Color Genomics, Ambry Genetics, and Mendelics Analise Genomica; as likely benign by Invitae and Integrated Genetics; and as uncertain significance by GeneDx, Counsyl, and 4 other submitters). The variant was identified in control databases in 261 of 277166 chromosomes at a frequency of 0.0009, 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 14 of 24018 chromosomes (freq: 0.0006), Other in 6 of 6468 chromosomes (freq: 0.0009), Latino in 2 of 34420 chromosomes (freq: 0.00006), European (Non-Finnish) in 153 of 126674 chromosomes (freq: 0.001), Ashkenazi Jewish in 2 of 10152 chromosomes (freq: 0.0002), East Asian in 58 of 18866 chromosomes (freq: 0.003), European (Finnish) in 5 of 25788 chromosomes (freq: 0.0002), and South Asian in 21 of 30780 chromosomes (freq: 0.0007). In a functional yeast assay, the response of the p.Arg180Cys CHEK2 variant to DNA damage was found to be decreased to 0.64 of wild type (1.00; Roeb 2012). A large study of the Breast Cancer Association Consortium found an association with breast cancer risk to be 1.33 odds ratio (Southey 2016). The p.Arg180 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2016	Variant summary: The CHEK2 c.538C>T (p.Arg180Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 168/123378 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0040472 (35/8648). This frequency is about 142 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature including breast and prostate cancer patients, however no co-segregation and limited co-occurrence data is provided by these studies. In addition, the variant is also reported in unaffected controls in these studies, suggesting the variant is not causitive in these populations. In a yeast-based functional assay, the variant had an intermediate response to DNA damage (Roeb_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS while one has classified it as likely benign. Taken together, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Case-control studies are inconclusive regarding association with breast cancer (Southy 2016, Decker 2017); Observed in individuals with breast, prostate, or ovarian cancer (Dong 2003, Dufault 2004, Kleibl 2008, Mohelnikova-Duchonova 2010, Le Calvez-Kelm 2011, Liu 2011, Mohamad 2015, Ng 2016, Chirasophon 2017, Xie 2017); Also known as CHEK2 c.667C>T (p.Arg223Cys); Published functional studies are inconclusive: intermediate response to DNA damage (Walsh 2011, Roeb 2012); This variant is associated with the following publications: (PMID: 26757417, 26483394, 28580595, 18085035, 30826992, 31060593, 25629968, 12533788, 22995991, 25980754, 25525159, 15095295, 20643596, 21618645, 24549055, 21244692, 27153395, 27498913, 22419737, 27595995, 21744992, 18058223, 18996005, 27621404, 23960188, 27783279, 22006311, 23555315, 28188963, 28452373, 28779002, 19782031, 29879026, 29470806, 30287823, 30851065, 31050813, 31422574, 29667044, 29263802, 32566746, 32041497, 33326660, 32906215) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 21, 2022	BS3_supporting -

Familial cancer of breast Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jul 08, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	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]. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 26, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 11, 2016	- -

Hereditary breast ovarian cancer syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	research	Molecular Oncology Research Center, Barretos Cancer Hospital	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	research	Cancer Genomics Group, Japanese Foundation For Cancer Research	May 01, 2019	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 14, 2022

- -

CHEK2-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Malignant tumor of prostate Uncertain:1

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

CHEK2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;.;D;D;.;D;.;.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.6	M;M;M;M;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;.;D;D;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D;D;D;D;.;D;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;.;D;D;D
Polyphen		0.64	P;D;P;P;P;P;D;.;.
Vest4		0.74
MVP		0.93
MPC		0.025
ClinPred		0.047	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.60

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: rs77130927; hg19: chr22-29121019; COSMIC: COSV60418236; COSMIC: COSV60418236;