22-28734447-G-T

Position:

• chr22-28734447-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007194.4(CHEK2):​c.275C>A​(p.Pro92His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.55

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.275C>A	p.Pro92His	missense_variant	2/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.275C>A	p.Pro92His	missense_variant	2/15	1	NM_007194.4	ENSP00000385747	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22419737, 19782031) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2017

The p.P92H variant (also known as c.275C>A), located in coding exon 1 of the CHEK2 gene, results from a C to A substitution at nucleotide position 275. The proline at codon 92 is replaced by histidine, an amino acid with some similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;T;.;.;D;D;D;.;T;D;T;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.2	M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;.;N;D;D;D;D;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.018	D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G	Uncertain	0.028	D;D;D;D;D;.;D;D;D;D;D;.;.
Polyphen		1.0	D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.47
MutPred		0.37		Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);
MVP		0.98
MPC		0.15
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.43

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: rs779269031; hg19: chr22-29130435;