rs148053495

chr22-28699894-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_007194.4(CHEK2):c.952C>T(p.Arg318Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,918 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.87

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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39679244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.952C>T	p.Arg318Cys	missense_variant	9/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.952C>T	p.Arg318Cys	missense_variant	9/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251470 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135904

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461814 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 21, 2016	- -
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	Invitae	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 318 of the CHEK2 protein (p.Arg318Cys). This variant is present in population databases (rs148053495, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal or breast cancer (PMID: 28135145, 30287823). ClinVar contains an entry for this variant (Variation ID: 128090). 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2021	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or colon cancer (Yurgleun 2017, Momozawa 2018); Published functional studies demonstrate a benign effect: growth rates similar to wild type (Delimitsou 2019); Also known as c.1081C>T (p.Arg361Cys); This variant is associated with the following publications: (PMID: 30851065, 22419737, 19782031, 30287823, 28135145) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2023	In the published literature, this variant has been reported in individuals with breast (PMID: 30287823 (2018)) or colorectal cancer (PMID: 28135145 (2017)). 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, 0.000012 (3/251470 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2023	The p.R318C variant (also known as c.952C>T), located in coding exon 8 of the CHEK2 gene, results from a C to T substitution at nucleotide position 952. The arginine at codon 318 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals diagnosed with breast, colorectal and/or prostate cancer (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095; Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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 not well 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2023	This missense variant replaces arginine with cysteine at codon 318 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). A functional study as shown this variant to have neutral effect in DNA damage response assay in yeast (PMID: 30851065). This variant has been observed in individuals affected with breast cancer (PMID: 30287823) and colorectal cancer (PMID: 28135145). This variant has been identified in 3/251470 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;T;.;T;.;T;.;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.59	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L;L;L;.;L;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.5	D;D;D;.;D;D;.;D;D;D;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D;.;D;T;.;T;D;D;.;D
Sift4G	Benign	0.064	T;T;T;.;T;D;.;T;T;D;.;.
Polyphen		1.0	D;D;D;.;D;D;D;D;D;.;.;.
Vest4		0.57
MVP		0.69
MPC		0.022
ClinPred		0.90	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.52

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: rs148053495; hg19: chr22-29095882; COSMIC: COSV60418538;