rs137853008

Positions:

• chr22-28734673-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_007194.4(CHEK2):​c.49G>T​(p.Ala17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A17G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -2.31

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
• PP5: Variant 22-28734673-C-A is Pathogenic according to our data. Variant chr22-28734673-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5595.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.030449927). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.49G>T	p.Ala17Ser	missense_variant	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.49G>T	p.Ala17Ser	missense_variant	2/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bone osteosarcoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.0030
DANN	Benign	0.34
DEOGEN2	Benign	0.12	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.71	.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.030	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.0	N;N;N;N;N;N;N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.020	N;N;N;N;N;.;N;N;N;N;N;.;.
REVEL	Benign	0.058
Sift	Benign	0.68	T;T;T;T;T;.;D;T;T;T;T;.;.
Sift4G	Benign	0.88	T;T;T;T;T;.;T;T;T;T;T;.;.
Polyphen		0.0	B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.083
MutPred		0.11		Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);Gain of phosphorylation at A17 (P = 0.0241);
MVP		0.59
MPC		0.019
ClinPred		0.026	T
GERP RS		-5.3
Varity_R		0.032
gMVP		0.12

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: rs137853008; hg19: chr22-29130661; COSMIC: COSV105247874; COSMIC: COSV105247874;