rs149501505

chr22-28687962-G-Achr22-28687962-G-Cchr22-28687962-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.1567C>T(p.Arg523Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,596,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R523H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 1.51

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=0.13364786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1567C>T	p.Arg523Cys	missense_variant	15/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1567C>T	p.Arg523Cys	missense_variant	15/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000343 AC: 8 AN: 233364 Hom.: 0 AF XY: 0.0000312 AC XY: 4 AN XY: 128244

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000660

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000312 AC: 45 AN: 1443868 Hom.: 0 Cov.: 30 AF XY: 0.0000306 AC XY: 22 AN XY: 718664

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000218 AC: 1

ExAC AF: 0.0000261 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 523 of the CHEK2 protein (p.Arg523Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with suspected Lynch syndrome and breast and/or cervical cancer (PMID: 25980754, 28503720, 30287823). ClinVar contains an entry for this variant (Variation ID: 141007). 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). 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	Counsyl	Apr 05, 2017	- -
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	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 20, 2022	This missense variant replaces arginine with cysteine at codon 523 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have demonstrated a neutral impact of this variant in DNA repair assays (PMID: 30851065). This variant has been reported in individuals affected with hereditary cancer (PMID: 25980754), and breast cancer (PMID: 28503720, 30287823). This variant has been identified in 9/264762 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The poor conservation of arginine at this position and no significant impact on CHEK2 function in experimental studies indicate that this variant is unlikely to be disease-causing. However, the available clinical 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	clinical testing	Ambry Genetics	Mar 06, 2023	The p.R523C variant (also known as c.1567C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1567. The arginine at codon 523 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in carriers and controls from studies of prostate, and breast and/or ovarian cancer cohorts (Rummel SK et al. Breast Cancer Res Treat, 2017; Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Aug;164:593-601; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Vargas-Parra G et al. Hum Mutat, 2020 Dec;41:2128-2142; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 27, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 14, 2023	In the published literature, this variant has been reported in individuals with Lynch syndrome (PMID: 25980754 (2015)), breast cancer (PMID: 30287823 (2020)), and hereditary cancer (PMID: 32906215 (2018)). Additionally, a functional study suggests that the variant is not damaging to CHEK2 protein expression or function (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.000086 (2/23334 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	Observed in patients with breast or prostate cancer, co-occurring with a BRCA2 pathogenic variant in at least one individual (Rummel et al., 2017; Momozawa et al., 2018; Delimitsou et al., 2019; Matejcic et al., 2020; Dorling et al., 2021); Published functional studies suggest no damaging effect: DNA damage response and cell growth similar to wild type in a yeast-based assay (Delimitsou et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 30851065, 29866652, 30287823, 31398194, 32906215, 33471991, 28503720, Vazquez-Juarez2022[abstract], 32832836) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 23, 2023

Variant summary: CHEK2 c.1567C>T (p.Arg523Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 233364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1567C>T has been reported in the literature in individuals affected with breast cancer and other tumor phenotypes (Yurgelun_2015, Rummel_2017, Momozawa_2018, Vargas-Parra_2020, Dorling_2021), however the variant was also reported in controls (e.g. Dorling_2021 and in the FLOSSIES database). In addition, in one of the reported cases a co-occurrence with another pathogenic variant has been reported (BRCA2 c.7007G>A, p.Arg2336His; Rummel_2017), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating in a yeast based DNA-damage assay that the variant showed similar function to the wild type (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 30287823, 28503720, 32906215, 25980754, 33471991). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, partly without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

CHEK2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2023

The CHEK2 c.1567C>T variant is predicted to result in the amino acid substitution p.Arg523Cys. This variant has been reported as uncertain significance in individuals with breast cancer, Lynch syndrome, or unspecified cancer (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Supplementary Data 1, Momozawa et al. 2018. PubMed ID: 30287823; Table S1, Vargas-Parra et al. 2020. PubMed ID: 32906215; Breast Cancer Association et al. 2021. PubMed ID: 33471991). This variant was also observed to co-occur with a pathogenic BRCA2 variant in an individual with breast cancer (Rummel et al. 2017. PubMed ID: 28503720). A yeast-based functional study showed that this variant does not affect protein function (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0086% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29083950-G-A) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141007/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

May 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;T;.;T;.;T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.077	N
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N;.;N;.;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N;N;.;N;N;.;N;N
REVEL	Benign	0.10
Sift	Benign	0.060	T;T;T;.;T;D;.;T;T
Sift4G	Benign	0.11	T;T;T;.;T;T;.;T;T
Polyphen		0.94	P;D;P;.;P;D;P;D;D
Vest4		0.11
MVP		0.78
MPC		0.080
ClinPred		0.17	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.22

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: rs149501505; hg19: chr22-29083950; COSMIC: COSV104653661;