chr22-28734442-C-A

Position:

• chr22-28734442-C-A

Variant summary

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

The NM_007194.4(CHEK2):​c.280G>T​(p.Ala94Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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.280G>T	p.Ala94Ser	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.280G>T	p.Ala94Ser	missense_variant	2/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461794 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2016

The p.A94S variant (also known as c.280G>T), located in coding exon 1 of the CHEK2 gene, results from a G to T substitution at nucleotide position 280. The alanine at codon 94 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 200000 alleles tested) in our clinical cohort. 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	0.52
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;.;.;D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.45	N;N;N;N;N;.;N;N;N;N;N;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.013	D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G	Uncertain	0.015	D;D;D;D;D;.;T;D;D;D;D;.;.
Polyphen		0.23	B;P;B;B;D;B;P;P;.;.;.;.;.
Vest4		0.20
MutPred		0.78		Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);Gain of glycosylation at A94 (P = 0.0535);
MVP		0.96
MPC		0.053
ClinPred		0.65	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.25

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: rs753860983; hg19: chr22-29130430;