rs1060502697

Positions:

• chr22-28734642-T-C
• chr22-28734642-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007194.4(CHEK2):​c.80A>G​(p.Gln27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.67

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23893994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.80A>G	p.Gln27Arg	missense_variant	2/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.80A>G	p.Gln27Arg	missense_variant	2/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727212

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: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The p.Q27R variant (also known as c.80A>G), located in coding exon 1 of the CHEK2 gene, results from an A to G substitution at nucleotide position 80. The glutamine at codon 27 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. 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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2018

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHEK2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with arginine at codon 27 of the CHEK2 protein (p.Gln27Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.060	D
MutationAssessor	Benign	1.5	L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.56	N;N;N;N;N;.;N;N;N;N;N;.;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G	Benign	0.12	T;T;T;T;T;.;D;T;D;D;D;.;.
Polyphen		0.60	P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.48
MutPred		0.28		Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);
MVP		0.98
MPC		0.15
ClinPred		0.87	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
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: rs1060502697; hg19: chr22-29130630;