22-28725305-G-T

Variant names:

• chr22-28725305-G-T
• rs1555927281
• NM_007194.4:c.382C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_007194.4(CHEK2):​c.382C>A​(p.Pro128Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. P128L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.35

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31056824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.382C>A	p.Pro128Thr	missense_variant	Exon 3 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.382C>A	p.Pro128Thr	missense_variant	Exon 3 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jul 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHEK2 c.382C>A (p.Pro128Thr) variant has been reported in the published literature in an individual with breast cancer (PMID: 37449874 (2023)). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 37449874 (2023)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast Uncertain:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 128 of the CHEK2 protein (p.Pro128Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 460828). 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 tolerated. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 31, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P128T variant (also known as c.382C>A), located in coding exon 2 of the CHEK2 gene, results from a C to A substitution at nucleotide position 382. The proline at codon 128 is replaced by threonine, 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	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Uncertain	0.45	T;.;T;T;.;T;.;.;.;D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	.;D;.;.;D;D;.;D;D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.3	M;M;M;M;.;M;M;.;.;.;.;.
PhyloP100		4.3
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N;D;N;N;D;.;D;N;D;.;.;.
REVEL	Uncertain	0.43
Sift	Benign	0.15	T;T;T;T;T;.;T;D;T;.;.;.
Sift4G	Benign	0.37	T;T;T;T;T;.;T;T;T;T;.;.
Polyphen		0.040	B;P;B;B;B;B;P;.;.;.;.;.
Vest4		0.52
MutPred		0.42		Gain of phosphorylation at P128 (P = 0.0424);Gain of phosphorylation at P128 (P = 0.0424);Gain of phosphorylation at P128 (P = 0.0424);Gain of phosphorylation at P128 (P = 0.0424);.;Gain of phosphorylation at P128 (P = 0.0424);Gain of phosphorylation at P128 (P = 0.0424);Gain of phosphorylation at P128 (P = 0.0424);.;Gain of phosphorylation at P128 (P = 0.0424);Gain of phosphorylation at P128 (P = 0.0424);Gain of phosphorylation at P128 (P = 0.0424);
MVP		0.97
MPC		0.040
ClinPred		0.41	T
GERP RS		5.9
Varity_R		0.54
gMVP		0.34
Mutation Taster		=68/32	polymorphism

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

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Other links and lift over

dbSNP: rs1555927281; hg19: chr22-29121293;