rs17879961

chr22-28725099-A-Cchr22-28725099-A-Gchr22-28725099-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_007194.4(CHEK2):c.470T>G(p.Ile157Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I157T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.65

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 7 ACMG points.

• PM1: In a hotspot region, there are 2 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-28725099-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity, risk_factor]. Clinvar id is 5591.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, Established_risk_allele=1, risk_factor=1, Pathogenic_low_penetrance=1, Likely_pathogenic=13, Uncertain_significance=9, not_provided=3}.
• PP5: Variant 22-28725099-A-C is Pathogenic according to our data. Variant chr22-28725099-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265327.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.470T>G	p.Ile157Ser	missense_variant	4/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.470T>G	p.Ile157Ser	missense_variant	4/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2015

This variant is denoted CHEK2 c.470T>G at the cDNA level, p.Ile157Ser (I157S) at the protein level, and results in the change of an Isoleucine to a Serine (ATT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, another non-conservative change at the same amino acid residue, CHEK2 Ile157Thr (I157T), has been observed in case-control studies at a higher frequency in breast and colon cancer cases than controls (Kilpivaara 2006, Suchy 2010, Desrichard 2011, Liu 2012, Han 2013). In addition, CHEK2 Ile157Thr was shown by a large meta-analysis to be associated with an increased risk of lobular breast cancer (OR>4.1) (Liu 2012). CHEK2 Ile157Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Ile157Ser occurs at a position that is highly conserved across species and is located within the FHA domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available information, we consider CHEK2 Ile157Ser to be a likely pathogenic variant. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CHEK2 p.Ile157Ser variant was not identified in the literature; however, a different CHEK2 p.Ile157 variant (p.Ile157Thr) was: the Ile157 residue is located in the FHA (forkhead-associated) domain and the p.Ile157Thr variant has been suggested to be functionally deficient in dimerization and autophoshorylation activity (Cai 2009); it is uncertain whether the p.Ile157Thr variant would have a similar predicted effect on protein function. The variant was identified in dbSNP (ID: rs17879961) as “With Likely pathogenic, Pathogenic allele” and ClinVar (classified likely pathogenic by GeneDx). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Ile157 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Ser variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 25, 2022

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. This variant disrupts the p.Ile157 amino acid residue in CHEK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 265327). This missense change has been observed in individual(s) with ovarian cancer (PMID: 30651582). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 157 of the CHEK2 protein (p.Ile157Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;T;T;.;T;.;.;D;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.85	L;L;L;L;.;L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.4	N;N;N;N;N;.;N;N;.;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.10	T;T;T;T;T;.;T;T;.;.;.
Sift4G	Benign	0.34	T;T;T;T;T;.;T;D;D;.;.
Polyphen		0.091	B;B;B;B;B;B;B;.;.;.;.
Vest4		0.67
MutPred		0.45		Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);.;Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);.;Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);
MVP		0.94
MPC		0.025
ClinPred		0.80	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs17879961; hg19: chr22-29121087;