chr22-28711950-T-A

Position:

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 (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:16

Conservation

PhyloP100: 4.86

Variant links:

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 links:

CHEK2 (HGNC:):

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.751A>T	p.Ile251Phe	missense_variant	6/15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.751A>T	p.Ile251Phe	missense_variant	6/15	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

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251360

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135866

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 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:

AN:

1461696

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727152

show subpopulations

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:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

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.:

Bravo

AF:

0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 10, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 08, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial cancer of breast

Uncertain:5

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	Labcorp Genetics (formerly Invitae), Labcorp	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	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 18, 2021	- -
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	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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 12, 2019	- -
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. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668: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

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

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;.;.;.;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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