22-28695860-C-T

Position:

• chr22-28695860-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007194.4(CHEK2):​c.1109G>A​(p.Gly370Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.09

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]

CHEK2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1109G>A	p.Gly370Glu	missense_variant	11/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1109G>A	p.Gly370Glu	missense_variant	11/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460296 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726628

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 2018

This variant is denoted CHEK2 c.1109G>A at the cDNA level, p.Gly370Glu (G370E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Gly370Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. CHEK2 Gly370Glu occurs at a position that is well conserved across species and is located in the protein kinase domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, we cannot determine whether CHEK2 Gly370Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2020

The p.G370E variant (also known as c.1109G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1109. The glycine at codon 370 is replaced by glutamic acid, an amino acid with similar properties. This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). Based on internal structural analysis, G370E is located in the DFG motif of CHEK2. This motif is important to catalysis and conformational changes (Kornev AP et al. Proc. Natl. Acad. Sci. U.S.A., 2006 Nov;103:17783-8; Oliver AW et al. EMBO J., 2006 Jul;25:3179-90; Lahiry P et al. Nat. Rev. Genet., 2010 Jan;11:60-74; Matijssen C et al. Bioorg. Med. Chem., 2012 Nov;20:6630-9; Silva-Santisteban MC et al. PLoS ONE, 2013 Jun;8:e65689). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 25, 2020

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 variant has been reported to affect CHEK2 protein function (PMID: 30851065). This variant has not been reported in the literature in individuals with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 128043). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 370 of the CHEK2 protein (p.Gly370Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T;.;T;.;T;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;D;.;D;.;D;D;D;.
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.1	M;.;M;.;M;.;M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;D;D;.;D;D;.;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0030	D;D;D;.;D;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;.;D;D;.;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D;D
Vest4		0.90
MutPred		0.99		Gain of ubiquitination at K373 (P = 0.0696);.;Gain of ubiquitination at K373 (P = 0.0696);.;Gain of ubiquitination at K373 (P = 0.0696);.;Gain of ubiquitination at K373 (P = 0.0696);.;.;
MVP		0.99
MPC		0.17
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.84

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: rs587780166; hg19: chr22-29091848;