rs587780179

chr22-28689152-G-Achr22-28689152-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_007194.4(CHEK2):c.1525C>T(p.Pro509Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,594,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P509L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3 O:1
• Conservation: PhyloP100: 0.464

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061661243).
• BP6: Variant 22-28689152-G-A is Benign according to our data. Variant chr22-28689152-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128063.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=3, not_provided=1}. Variant chr22-28689152-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1525C>T	p.Pro509Ser	missense_variant	14/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1525C>T	p.Pro509Ser	missense_variant	14/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151886 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000813 AC: 19 AN: 233628 Hom.: 0 AF XY: 0.0000779 AC XY: 10 AN XY: 128314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000851

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000985 AC: 142 AN: 1442138 Hom.: 0 Cov.: 29 AF XY: 0.000100 AC XY: 72 AN XY: 717936

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: 0.000290

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151886 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74154

Gnomad4 AFR AF: 0.0000242

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: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000113 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 509 of the CHEK2 protein (p.Pro509Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, Lynch syndrome, ovarian cancer, prostate cancer, skin cancer, and/or uterine cancer (PMID: 18571837, 25980754, 28051113, 29596542, 31050813). ClinVar contains an entry for this variant (Variation ID: 128063). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31409080). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2021	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: intermediate to normal activity with respect to DNA damage response and kinase activity (Delimitsou 2019, Kleiblova 2019); Observed in individuals with breast, ovarian, prostate, and other cancers (Tischkowitz 2008, Yurgelun 2015, Castellanos 2017, Kleiblova 2019); This variant is associated with the following publications: (PMID: 32906215, 27535533, 31050813, 31422574, 30851065, 29596542, 28420421, 28051113, 18571837, 25980754) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2024	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 03, 2016	- -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C1836482:Li-Fraumeni syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 25, 2021

Variant summary: CHEK2 c.1525C>T (p.Pro509Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 263796 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (9.5e-05 vs 0.00031), allowing no conclusion about variant significance. c.1525C>T has been reported in the literature in individuals affected with various tumor phenotypes (Castellanos_2015, Yurgelun_2015, Tischkowitz_2008). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating decreased function in a yeast based DNA-damage assay that indicated an intermediate functionality for the variant (Delimitsou_2019). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=8) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CHEK2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2022

The CHEK2 c.1525C>T variant is predicted to result in the amino acid substitution p.Pro509Ser. This variant was reported in a patient with prostate cancer of Ashkenazi Jewish origin (Tischkowitz et al. 2008, PubMed ID: 18571837) and also in two individuals with suspected Lynch syndrome (Yurgelun et al. 2015, Supplemental Table 2, PubMed ID: 25980754). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29085140-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128063/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 11-29-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	3.0
Dann	Benign	0.50
DEOGEN2	Benign	0.34	T;.;T;.;T;.;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.063	N
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.062	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;L;.;L;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;D;D;.;D;D;.;D;D
REVEL	Benign	0.088
Sift	Benign	0.081	T;T;T;.;T;T;.;D;T
Sift4G	Benign	0.10	T;T;T;.;T;T;.;T;T
Polyphen		0.0	B;B;B;.;B;B;B;B;B
Vest4		0.17
MutPred		0.18		Gain of phosphorylation at P509 (P = 0.0378);.;Gain of phosphorylation at P509 (P = 0.0378);.;Gain of phosphorylation at P509 (P = 0.0378);.;Gain of phosphorylation at P509 (P = 0.0378);.;.;
MVP		0.30
MPC		0.020
ClinPred		0.032	T
GERP RS		-2.3
Varity_R		0.11
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587780179; hg19: chr22-29085140; COSMIC: COSV60417044;