rs587780189

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_StrongBS2_Supporting

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 Conflicting classifications of pathogenicity (no stars). 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:17

Conservation

PhyloP100: 4.86

Publications

15 publications found

Variant links:

COSMIC-nc: COSV106101398

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 Gene-Disease associations (from GenCC):

CHEK2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
Li-Fraumeni syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

BS2

High AC in GnomAd4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.751A>T	p.Ile251Phe	missense_variant	Exon 6 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.751A>T	p.Ile251Phe	missense_variant	Exon 6 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251360

AF XY:

0.0000147

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461696

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1111940

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:1Uncertain:4

May 30, 2025

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 34903604, 37449874]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. -

Jul 02, 2018

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 05, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:5

Feb 21, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with a personal or family history of breast, prostate, colorectal, or other cancers, as well as in healthy controls (PMID: 12533788, 22114986, 21244692, 25980754, 27498913, 27978560, 28135145, 29522266, 33471991, 34326862); Published functional studies are inconclusive: demonstrates intermediate impact on auto-phosphorylation, impaired kinase activity against KAP1, and showed reduced response to DNA damage in a yeast-based assay (PMID: 30851065, 34903604, 37449874); Also known as c.880A>T, p.(I294F); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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, 35441217, 22419737, 19782031, 37449874, 34326862) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CHEK2 c.751A>T (p.Ile251Phe) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 34326862 (2021), 29522266 (2018), 26787654 (2016), 33471991 (2011), 22114986 (2011)), colorectal cancer (PMIDs: 28135145 (2017), 27978560 (2016)), suspected Lynch syndrome (PMID: 25980754 (2015)), renal cell carcinoma (PMID: 35441217 (2022)), prostate cancer (PMID: 12533788 (2003)), as well as in a reportedly healthy individual (PMID: 21244692 (2011)). This variant has been found to co-occur with a BRCA2 pathogenic variant in an individual with colorectal cancer (PMID: 27978560 (2016)), and with a CHEK2 pathogenic variant in an individual with breast cancer (PMID: 34326862 (2021)), suggesting it may not be the primary cause of disease. Functionally, however, this variant has been reported to cause reduced cell growth and CHEK2 phosphorylation activity in experimental studies (PMIDs: 34903604 (2021), 30851065 (2019)). The frequency of this variant in the general population, 0.000039 (5/129140 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2017

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:4

Jan 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 shown impaired kinase activity toward a downstream target protein Kap1 despite intact or intermediate auto-phosphorylation of CHEK2 in mouse embryonic stem cells and human cell assays (PMID: 34903604, 37449874). 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 reported in two large breast cancer case-control meta-analyses: in 3/60466 cases and 0/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000193) and in 13/73048 cases and 5/88658 controls (PMID: 37449874). 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. -

Jan 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dec 18, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Oct 07, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_moderate, PM1, PM2_supporting c.751A>T, located in exon 6 of the CHEK2 gene, is predicted to result in the substitution of Isoleucine by Phenylalanine at codon 251, p.(Ile251Phe). It affects a highly conserved amino acid of the kinase-domain (226-486 aa) (PM1). This variant is found in 4/268220 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.426) for this variant is indeterminate regarding the effect that it may have on protein function according Pejaver 2022 thresholds (PMID: 36413997). Functional studies demonstrated intermediate impact on auto-phosphorylation, impaired kinase activity against KAP1, and reduced response to DNA damage (PMID: 30851065, 34903604, 37449874) (PS3_moderate). It has been reported in ClinVar as an uncertain significance. Based on the currently available information, c.751A>T is classified as an uncertain significance variant according to ACMG guidelines. -

not specified

Uncertain:2

Nov 12, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition

Uncertain:1

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CHEK2-related cancer predisposition

Uncertain:1

Mar 30, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

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

LIST_S2

Uncertain

0.94

.;D;.;D;.;D;D;D;.;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.79

MutationAssessor

Benign

2.0

M;M;M;.;M;.;M;.;M;.;.;.;.

PhyloP100

4.9

PrimateAI

Uncertain

0.75

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

GERP RS

5.3

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.72

Mutation Taster

=0/100

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over