22-28699883-T-G

Variant summary

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

The NM_007194.4(CHEK2):c.963A>C(p.Glu321Asp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E321A) has been classified 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: 1.93

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, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.963A>C	p.Glu321Asp	missense_variant	9/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.963A>C	p.Glu321Asp	missense_variant	9/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The p.E321D variant (also known as c.963A>C), located in coding exon 8 of the CHEK2 gene, results from an A to C substitution at nucleotide position 963. The glutamic acid at codon 321 is replaced by aspartic acid, an amino acid with highly 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T;.;T;.;T;.;.;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M;M;M;.;M;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N;N;N;.;N;N;.;N;N;N;.;D
REVEL	Uncertain	0.35
Sift	Benign	0.090	T;T;T;.;T;D;.;D;T;D;.;T
Sift4G	Uncertain	0.053	T;T;T;.;T;D;.;D;T;D;.;.
Polyphen		0.87	P;P;P;.;P;P;P;P;P;.;.;.
Vest4		0.86
MutPred		0.92		Gain of MoRF binding (P = 0.1291);Gain of MoRF binding (P = 0.1291);Gain of MoRF binding (P = 0.1291);.;Gain of MoRF binding (P = 0.1291);.;Gain of MoRF binding (P = 0.1291);.;Gain of MoRF binding (P = 0.1291);.;.;.;
MVP		0.66
MPC		0.037
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.81
gMVP		0.59

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: rs876659458; hg19: chr22-29095871;