22-28734669-C-G

Variant names:

• chr22-28734669-C-G
• rs151218932
• NM_007194.4:c.53G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_007194.4(CHEK2):​c.53G>C​(p.Cys18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. C18F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.412
• Publications: 10 publications found

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]

CHEK2 Gene-Disease associations (from GenCC):

• CHEK2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 39 uncertain in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0604316).
• BP6: Variant 22-28734669-C-G is Benign according to our data. Variant chr22-28734669-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 491618.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.53G>C	p.Cys18Ser	missense_variant	Exon 2 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.53G>C	p.Cys18Ser	missense_variant	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Feb 28, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 08, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with serine at codon 18 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial cancer of breast Uncertain:1

Apr 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 491618). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 18 of the CHEK2 protein (p.Cys18Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.49
DANN	Benign	0.43
DEOGEN2	Benign	0.15	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.62	.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.060	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.0	L;L;L;L;L;L;L;L;.;.;.;.;.
PhyloP100		-0.41
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.34	N;N;N;N;N;.;N;N;N;N;D;.;.
REVEL	Benign	0.076
Sift	Benign	0.20	T;T;T;T;T;.;D;T;T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;.;T;T;T;T;T;.;.
Polyphen		0.0	B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.085
MutPred		0.23		Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);Gain of phosphorylation at C18 (P = 0.0094);
MVP		0.48
MPC		0.021
ClinPred		0.047	T
GERP RS		-7.8
PromoterAI		-0.0064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.12
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs151218932; hg19: chr22-29130657; COSMIC: COSV60427130; COSMIC: COSV60427130;