rs730881697

Variant names:

• chr22-28734445-A-C
• NM_007194.4:c.277T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-28734445-A-C
• chr22-28734445-A-G
• chr22-28734445-A-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.277T>G​(p.Trp93Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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, single submitter U:1
• Conservation: PhyloP100: 5.92

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.277T>G	p.Trp93Gly	missense_variant	Exon 2 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.277T>G	p.Trp93Gly	missense_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 24, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W93G variant (also known as c.277T>G), located in coding exon 1 of the CHEK2 gene, results from a T to G substitution at nucleotide position 277. The tryptophan at codon 93 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D;.;D;D;.;D;.;.;.;.;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	.;T;.;.;T;T;D;.;D;D;T;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;.;D;D;D;D;D;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;.;.
Polyphen		1.0	D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.64
MutPred		0.79		Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);
MVP		0.93
MPC		0.19
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29130433;