rs759734429

chr22-28719464-G-Achr22-28719464-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007194.4(CHEK2):c.614C>T(p.Thr205Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,441,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T205A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.61

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.614C>T	p.Thr205Ile	missense_variant	5/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.614C>T	p.Thr205Ile	missense_variant	5/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1441564 Hom.: 0 Cov.: 28 AF XY: 0.00000558 AC XY: 4 AN XY: 716232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000835 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 22, 2021

DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.614C>T, in exon 5 that results in an amino acid change, p.Thr205Ile. This sequence change has been described in the gnomAD database with a frequency of 0.001% in the non-Finnish European subpopulation (dbSNP rs759734429). The p.Thr205Ile change affects a moderately conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr205Ile substitution. This sequence change has been identified in an individual with a personal history of breast and thyroid cancer (PMID: 34130653). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr205Ile change remains unknown at this time. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The p.T205I variant (also known as c.614C>T), located in coding exon 4 of the CHEK2 gene, results from a C to T substitution at nucleotide position 614. The threonine at codon 205 is replaced by isoleucine, an amino acid with 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. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2023

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: 530183). 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. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 5 (Invitae). 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 205 of the CHEK2 protein (p.Thr205Ile). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;T;T;.;T;.;.;.
Eigen	Benign	0.046
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Benign	1.3	L;L;L;L;.;L;.;L;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N;N;N;N;.;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.13	T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;.;T;T;T
Polyphen		0.086	B;B;B;B;B;B;P;B;.
Vest4		0.56
MutPred		0.44		Loss of phosphorylation at T205 (P = 0.0896);Loss of phosphorylation at T205 (P = 0.0896);Loss of phosphorylation at T205 (P = 0.0896);Loss of phosphorylation at T205 (P = 0.0896);.;Loss of phosphorylation at T205 (P = 0.0896);.;Loss of phosphorylation at T205 (P = 0.0896);.;
MVP		0.94
MPC		0.027
ClinPred		0.35	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -6

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

Publications

LitVar

Other links and lift over

dbSNP: rs759734429; hg19: chr22-29115452; COSMIC: COSV60425504; COSMIC: COSV60425504;