chr22-28695872-A-T

Variant names:

• chr22-28695872-A-T
• rs786202147
• NM_007194.4:c.1097T>A

Variant summary

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

The NM_007194.4(CHEK2):​c.1097T>A​(p.Ile366Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 missense, splice_region
• Scores: Splicing: ADA: 0.8840
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 8.08

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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1097T>A	p.Ile366Asn	missense_variant, splice_region_variant	Exon 11 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1097T>A	p.Ile366Asn	missense_variant, splice_region_variant	Exon 11 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Mar 05, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I366N variant (also known as c.1097T>A), located in coding exon 10 of the CHEK2 gene, results from a T to A substitution at nucleotide position 1097. The isoleucine at codon 366 is replaced by asparagine, an amino acid with dissimilar 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:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I366N variant (also known as c.1097T>A), located in coding exon 10 of the CHEK2 gene, results from a T to A substitution at nucleotide position 1097. The isoleucine at codon 366 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. This variant was not found in gnomAD genomes. There is a ClinVar entry for this variant with submissions list it as variant of uncertain significance. In addition, the insilico prediction for this alteration showed 12 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT; and two benign from DEOGEN2 and FATHMM. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 366 of the CHEK2 protein (p.Ile366Asn). 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: 489872). 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. 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. -

Li-Fraumeni syndrome 2 Uncertain:1

Aug 18, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 22, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22419737, 19782031, 31925297) -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Uncertain:1

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;T;.;T;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.44	.;T;.;D;.;D;D;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.6	H;.;H;.;H;.;H;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.1	D;D;D;.;D;D;.;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;.;D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;D;D;.;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D;D
Vest4		0.92
MutPred		0.89		Loss of stability (P = 0.0164);.;Loss of stability (P = 0.0164);.;Loss of stability (P = 0.0164);.;Loss of stability (P = 0.0164);.;.;
MVP		0.98
MPC		0.19
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.010		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: rs786202147; hg19: chr22-29091860;