rs1060502700

Positions:

• chr22-28725358-T-C
• chr22-28725358-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_007194.4(CHEK2):​c.329A>G​(p.Asn110Ser) 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. 16/21 in silico tools predict 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. N110D) 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:2
• Conservation: PhyloP100: 1.93

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 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_007194.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15004542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.329A>G	p.Asn110Ser	missense_variant	3/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.329A>G	p.Asn110Ser	missense_variant	3/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 110 of the CHEK2 protein (p.Asn110Ser). 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: 410031). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The p.N110S variant (also known as c.329A>G), located in coding exon 2 of the CHEK2 gene, results from an A to G substitution at nucleotide position 329. The asparagine at codon 110 is replaced by serine, an amino acid with highly similar properties. This alteration was identified in a cohort of 481 Chinese breast cancer patients with family history of breast/ovarian cancer (Wang J et al. Cancer Med, 2019 May;8:2074-2084). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.065
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.;T;T;.;T;.;.;.;T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L;L;L;L;.;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;N;N;N;N;.;N;N;N;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.42	T;T;T;T;T;.;T;D;T;.;.;.
Sift4G	Benign	0.66	T;T;T;T;T;.;T;T;T;T;.;.
Polyphen		0.15	B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.27
MutPred		0.43		Gain of catalytic residue at N110 (P = 0.064);Gain of catalytic residue at N110 (P = 0.064);Gain of catalytic residue at N110 (P = 0.064);Gain of catalytic residue at N110 (P = 0.064);.;Gain of catalytic residue at N110 (P = 0.064);Gain of catalytic residue at N110 (P = 0.064);Gain of catalytic residue at N110 (P = 0.064);.;Gain of catalytic residue at N110 (P = 0.064);Gain of catalytic residue at N110 (P = 0.064);Gain of catalytic residue at N110 (P = 0.064);
MVP		0.95
MPC		0.020
ClinPred		0.11	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs1060502700; hg19: chr22-29121346;