rs74751600

chr22-28695852-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_007194.4(CHEK2):c.1117A>G(p.Lys373Glu) variant causes a missense change. 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. K373R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.21

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_007194.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011854082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1117A>G	p.Lys373Glu	missense_variant	11/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1117A>G	p.Lys373Glu	missense_variant	11/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152072 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000626 AC: 886 AN: 1414758 Hom.: 0 Cov.: 31 AF XY: 0.000563 AC XY: 397 AN XY: 705378

Gnomad4 AFR exome AF: 0.00151

Gnomad4 AMR exome AF: 0.0000899

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.000378

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000710

Gnomad4 OTH exome AF: 0.000477

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74280

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00121 Hom.: 0

ExAC AF: 0.0260 AC: 3161

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 30, 2023	This missense change has been observed in individual(s) with breast cancer (PMID: 28135048). This variant is also known as as c.1246A>G (p.Lys416Glu). ClinVar contains an entry for this variant (Variation ID: 481100). 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 disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 27716909). 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. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 373 of the CHEK2 protein (p.Lys373Glu). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 24, 2018	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 29, 2022	The p.K373E variant (also known as c.1117A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1117. The lysine at codon 373 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 4 individuals of Chinese descent with triple negative breast cancer, but was not identified in the Asian control population in this study (Liu et al. Cancer Med. 2017 Mar;6(3):547-554). This alteration has been reported as a somatic alteration and was shown to result in disrupted CHK2 autophosphorylation and disrupted CHK2 kinase activity (Higashiguchi M et al. FEBS Lett., 2016 Oct). This alteration has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and 0.0000 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Of note, this alteration is also described in the literature as c.1246A>G using the isoform NM_001005735.1. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting 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	Dec 01, 2023	This missense variant replaces lysine with glutamic acid at codon 373 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 reported that this variant impacts CHEK2 function in autophosphorylation and phosphorylation of KAP1 (PMID: 27716909). This variant has been reported in at least 5 individuals affected with breast cancer (PMID: 28135048, 30287823) and in a breast cancer case-control meta-analysis in 20/73048 female BC cases and 3/88658 unaffected controls with OR 10.8 (95% CI 3.20-56.75) (PMID: 37449874). This variant has not been identified 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

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T;.;T;.;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.66	N;.;N;.;N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D;D;D;.;D;D;.;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D;D;.;D;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;.;D;D;.;D;D
Polyphen		0.99	D;D;D;.;D;D;D;D;D
Vest4		0.52
MPC		0.17
ClinPred		0.33	T
GERP RS		5.9
Varity_R		0.95
gMVP		0.73

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: rs74751600; hg19: chr22-29091840; COSMIC: COSV60415074; COSMIC: COSV60415074;