rs587780189

chr22-28711950-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_007194.4(CHEK2):c.751A>T(p.Ile251Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I251T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:16
• Conservation: PhyloP100: 4.86

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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.751A>T	p.Ile251Phe	missense_variant	6/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.751A>T	p.Ile251Phe	missense_variant	6/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152230 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251360 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135866

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: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461696 Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 727152

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: 0.0000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74378

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: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 251 of the CHEK2 protein (p.Ile251Phe). This variant is present in population databases (rs587780189, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer and breast cancer (PMID: 12533788, 22114986, 25980754, 27978560). ClinVar contains an entry for this variant (Variation ID: 128086). 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 disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 34903604). 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	Counsyl	Jan 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 25, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	Observed in individuals with a personal or family history of breast, prostate, colorectal, or other cancers, as well as in healthy controls (Dong et al., 2003; Desrichard et al., 2011; Le Calvez-Kelm et al., 2011; Yurgelun et al., 2015; Ballinger et al., 2016; Pearlman et al., 2017; Yurgelun et al., 2017; Hauke et al., 2018; Dorling et al., 2021); Published functional studies demonstrate reduced response to DNA damage in a yeast-based assay and intermediate impact on kinase activity in a mouse ES study (Delimitsou et al., 2019; Boonen et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31398194, 12533788, 22114986, 25980754, 26787654, 27978560, 21244692, 28135145, 27498913, 29596542, 29522266, 28843361, 30851065, 34903604, 33471991, 35127508, 22419737, 19782031, 35441217) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 08, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2022	Variant summary: CHEK2 c.751A>T (p.Ile251Phe) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 255478 control chromosomes (gnomAD, and publication data). c.751A>T has been reported in the literature in individuals undergoing multigene panel testing within settings of breast cancer (e.g. Desrichard_2011, Young_2016, Hauke_2018, Dorling_2021), in a family with prostate cancer where this variant did not segregate with disease among two genotyped affected family members (Dong_2003), and in individuals with colorectal cancers (Yurgelun_2015, Yurgelun_2017, Pearlman_2016). At least one co-occurrence with another pathogenic variant has been reported in a female with MMR proficient colorectal cancer (BRCA2 c.1755_1759del, p.K585Nfs*3, Pearlman_2016), providing supporting evidence for a benign role. These data do not allow clear conclusions about variant significance. At least two functional studies reported experimental evidence evaluating an impact on protein function, and assigned a "damaging" functional classification in a yeast-based functional assay evaluating the DNA repair-ability after chemically induced DNA damage (Delimitsou_2019), while another study reported moderately reduced autophosphorylation, with severely reduced (~15%) kinase activity toward the phosphorylation of target protein KAP1 in a CHEK2 knockout mouse embryonic stem cell system (Boonen_2022). Nine ClinVar submitters have assessed this variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 12, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This missense variant replaces isoleucine with phenylalanine at codon 251 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the mutant protein to be non-functional in a yeast complementation assay (PMID: 30851065) and to show impaired kinase activity toward a downstream target protein Kap1 despite intact auto-phosphorylation (PMID: 34903604). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 29522266; Color internal data), colorectal cancer (PMID: 27978560), suspected Lynch syndrome (PMID: 25980754) and prostate cancer (PMID 12533788). Some of these affected individuals also carried a pathogenic variant in a different gene that could explain the observed phenotype (PMID: 2797856; Color internal data). This variant has also been observed in an unaffected control individual (PMID: 21244692). This variant has been identified in 5/282756 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 09, 2024	The p.I251F variant (also known as c.751A>T), located in coding exon 5 of the CHEK2 gene, results from an A to T substitution at nucleotide position 751. The isoleucine at codon 251 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration is located in the CHK2 kinase domain and has been detected in cohorts of individuals with hereditary breast cancer, colorectal cancer younger than 50 years, sarcoma, as well as familial prostate cancer (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). In one case-control study, this alteration was not detected in 1313 breast cancer patients diagnosed at or before age 45, but it was seen in 1/1123 healthy controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). This alteration behaved as non-functional in an in vivo yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648). This alteration was also reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 18, 2021	- -

Familial cancer of breast;C0346629:Colorectal cancer;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

Apr 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;T;.;T;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	M;M;M;.;M;.;M;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D;D;D;.;D;D;.;D;D;D;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;D;.;D;T;.;T;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;.;D;D;.;D;D;D;.;.;D
Polyphen		1.0	D;D;D;.;D;D;D;D;D;.;.;.;.
Vest4		0.85
MutPred		0.91		Loss of methylation at K249 (P = 0.0907);Loss of methylation at K249 (P = 0.0907);Loss of methylation at K249 (P = 0.0907);.;Loss of methylation at K249 (P = 0.0907);.;Loss of methylation at K249 (P = 0.0907);.;Loss of methylation at K249 (P = 0.0907);.;.;.;.;
MVP		0.86
MPC		0.18
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.72

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: rs587780189; hg19: chr22-29107938;