rs1060502696

Positions:

• chr22-28734607-A-G
• chr22-28734607-A-T

Variant summary

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

The NM_007194.4(CHEK2):​c.115T>C​(p.Ser39Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.07

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26039103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.115T>C	p.Ser39Pro	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.115T>C	p.Ser39Pro	missense_variant	2/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727238

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 2023	The p.S39P variant (also known as c.115T>C), located in coding exon 1 of the CHEK2 gene, results from a T to C substitution at nucleotide position 115. The serine at codon 39 is replaced by proline, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 Nov;54:732-741). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 27, 2023	This missense variant replaces serine with proline at codon 39 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). In CHEK2-complementation assays in human CHEK2-knockout cells, this variant did not impact CHK2 autophosphorylation or KAP1 phosphorylation (PMID: 37449874). This variant has been reported in two large breast cancer case-control meta analyses; in 1/73048 cases and 1/88658 controls (PMID: 37449874), and 4/60466 cases and 0/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000254). 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 16, 2023	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 410024). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 39 of the CHEK2 protein (p.Ser39Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	2.0	M;M;M;M;M;M;M;M;.;.;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.030	N;N;N;N;N;.;N;N;N;N;D;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.025	D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G	Benign	0.26	T;T;T;T;T;.;T;T;T;T;T;.;.
Polyphen		0.99	D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.40
MutPred		0.20		Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);Loss of phosphorylation at S39 (P = 0.0034);
MVP		0.97
MPC		0.067
ClinPred		0.75	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.33

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: rs1060502696; hg19: chr22-29130595;