22-28695242-G-C

Position:

• chr22-28695242-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007194.4(CHEK2):​c.1260C>G​(p.Cys420Trp) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. C420Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 missense, splice_region
• Scores: Splicing: ADA: 0.9774
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1260C>G	p.Cys420Trp	missense_variant, splice_region_variant	12/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1260C>G	p.Cys420Trp	missense_variant, splice_region_variant	12/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 410037). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 420 of the CHEK2 protein (p.Cys420Trp). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;T;.;T;.;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;.;D;.;D;D;D;.
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.5	L;.;L;.;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.7	D;D;D;.;D;D;.;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.014	D;D;D;.;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;.;D;D;.;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D;D
Vest4		0.94
MutPred		0.60		Loss of stability (P = 0.0664);.;Loss of stability (P = 0.0664);.;Loss of stability (P = 0.0664);.;Loss of stability (P = 0.0664);.;.;
MVP		0.92
MPC		0.17
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.69
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: rs762205611; hg19: chr22-29091230;