22-28694032-C-G

Position:

• chr22-28694032-C-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.1461G>C​(p.Gln487His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to 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. Q487R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.88

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1461G>C	p.Gln487His	missense_variant, splice_region_variant	13/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1461G>C	p.Gln487His	missense_variant, splice_region_variant	13/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2021

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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHEK2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 487 of the CHEK2 protein (p.Gln487His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 13 of the CHEK2 coding sequence, which is part of the consensus splice site for this exon. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2020

The c.1461G>C variant (also known as p.Q487H), located in coding exon 12 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1461. The amino acid change results in glutamine to histidine at codon 487, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.37
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;T;.;T;.;T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	.;D;.;D;.;D;D;D;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.0	L;.;L;.;L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D;D;D;.;D;D;.;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D;D;D;.;D;D;.;D;D
Sift4G	Uncertain	0.023	D;D;D;.;D;D;.;D;D
Polyphen		0.36	B;D;B;.;B;D;B;D;D
Vest4		0.68
MutPred		0.20		Loss of stability (P = 0.1678);.;Loss of stability (P = 0.1678);.;Loss of stability (P = 0.1678);.;Loss of stability (P = 0.1678);.;.;
MVP		0.67
MPC		0.14
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502701; hg19: chr22-29090020;