rs587781879

chr22-28725304-G-Achr22-28725304-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_007194.4(CHEK2):c.383C>T(p.Pro128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,940 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P128T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.24

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 1 ACMG points.

• PM1: In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 27 pathogenic changes around while only 5 benign (84%) in NM_007194.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.3091727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.383C>T	p.Pro128Leu	missense_variant	3/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.383C>T	p.Pro128Leu	missense_variant	3/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461770 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727178

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 29, 2022	The p.P128L variant (also known as c.383C>T), located in coding exon 2 of the CHEK2 gene, results from a C to T substitution at nucleotide position 383. The proline at codon 128 is replaced by leucine, an amino acid with similar properties. 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	Aug 31, 2023	This missense variant replaces proline with leucine at codon 128 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). A functional study has shown this variant protein does not impact protein localization or kinase activity (PMID: 37449874). In a large breast cancer case-control meta analysis conducted by the ENIGMA consortium, this variant was reported in 3/73048 cases and 1/88658 unaffected controls (PMID: 37449874). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 128 of the CHEK2 protein (p.Pro128Leu). 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: 141613). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Uncertain	0.55	D;.;D;D;.;D;.;.;.;D;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0031
FATHMM_MKL	Benign	0.70	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.017	D
MutationAssessor	Benign	1.6	L;L;L;L;.;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;.;D;D;D;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.10	T;T;T;T;T;.;T;T;D;.;.;.
Sift4G	Benign	0.20	T;T;T;T;T;.;T;T;T;T;.;.
Polyphen		0.0030	B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.36
MutPred		0.50		Loss of methylation at K131 (P = 0.0829);Loss of methylation at K131 (P = 0.0829);Loss of methylation at K131 (P = 0.0829);Loss of methylation at K131 (P = 0.0829);.;Loss of methylation at K131 (P = 0.0829);Loss of methylation at K131 (P = 0.0829);Loss of methylation at K131 (P = 0.0829);.;Loss of methylation at K131 (P = 0.0829);Loss of methylation at K131 (P = 0.0829);Loss of methylation at K131 (P = 0.0829);
MVP		0.97
MPC		0.022
ClinPred		0.70	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.38

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: rs587781879; hg19: chr22-29121292; COSMIC: COSV60426648; COSMIC: COSV60426648;