22-28694072-C-T

Position:

chr22-28694072-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM5PP3_ModeratePP5

The NM_007194.4(CHEK2):c.1421G>A(p.Arg474His) variant causes a missense change. The variant allele was found at a frequency of 0.0000457 in 1,596,022 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. R474C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:10B:1O:1

Conservation

PhyloP100: 5.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-28694073-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128059.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=9}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 22-28694072-C-T is Pathogenic according to our data. Variant chr22-28694072-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126910.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_benign=1, Likely_pathogenic=7, Uncertain_significance=8}. Variant chr22-28694072-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1421G>A	p.Arg474His	missense_variant	13/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1421G>A	p.Arg474His	missense_variant	13/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000642

AC:

AN:

233796

Hom.:

AF XY:

0.0000390

AC XY:

AN XY:

128358

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000919

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000436

AC:

AN:

1443868

Hom.:

Cov.:

AF XY:

0.0000487

AC XY:

AN XY:

718702

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.000361

AC:

ESP6500EA

AF:

0.000213

AC:

ExAC

AF:

0.0000693

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:10Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:1Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 474 of the CHEK2 protein (p.Arg474His). This variant is present in population databases (rs121908706, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and non-Hodgkin lymphoma (PMID: 25186627, 25452441, 26506619, 30303537, 30333958, 30613976, 31050813, 34903604). This variant is also known as p.Arg517His. ClinVar contains an entry for this variant (Variation ID: 126910). 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: 31050813, 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	Baylor Genetics	Feb 07, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	The p.R474H variant (also known as c.1421G>A), located in coding exon 12 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1421. The arginine at codon 474 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in a familial breast and ovarian cancer patient (reported as c.1550G>A, p.Arg517His under reference sequence NM_001005735.1) and reported in the germline of 1/340 non-Hodgkin lymphoma patients and in 0/445 non-cancer controls (Havranek O et al. PLoS ONE. 2015 Oct;10:e0140819; Brovkina OI et al. Front Oncol. 2018 Oct 2;8:421). This amino acid position is highly conserved in available vertebrate species. This variant has an entry in ClinVar with 9 submissions, one pathogenic, on “not provided”, and 7 uncertain significance, one star. Alternative variant chr22:29090060 C⇒A (Arg474Leu) is classified Likely Pathogenic, 0 stars, by ClinVar In addition, this alteration is predicted to be pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs 1 benign prediction from PrimateAI. Therefore, this variant is classified as of uncertain significance. -
Likely benign, flagged submission	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]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 22, 2024	Criteria applied: PS3,PM5,PS4_SUP -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 25, 2017	- -

not provided

Pathogenic:3Uncertain:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2024	Published functional studies demonstrate a damaging effect: decreased autophosphorylation, kinase activity, and protein stability (PMID: 31050813, 34903604, 37449874); 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); Also known as c.1550G>A p.(R517H); This variant is associated with the following publications: (PMID: 26506619, 25452441, 31050813, 30303537, 30333958, 30374176, 31422574, 25186627, 30613976, 33471991, 29522266, 25085752, 34903604, 35534704, 34326862, 36288950, 37449874, 22419737, 19782031) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
not provided, no classification provided	literature only	Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 08, 2020	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 02, 2023	This missense variant replaces arginine with histidine at codon 474 of the CHEK2 protein. This variant impacts a highly conserved arginine in the kinase domain of the protein (PMID: 15060014, 19782031). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts CHEK2 function in kinase assays and DNA damage response performed in mouse embryonic stem cells, yeast and in vitro models (PMID: 30851065, 31050813, 34903604). This variant has been detected in a breast cancer case-control meta-analysis in 18/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000183). This variant also has been reported in individuals affected with breast cancer (PMID: 25186627, 25452441, 29522266, 30303537), a suspected hereditary breast and ovarian cancer family (PMID: 30333958), an individual affected with non-Hodgkin lymphoma (PMID: 26506619) and an individual without cancer diagnosis (PMID: 31422574). This variant has been identified in 19/265178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 29, 2023	The p.R474H variant (also known as c.1421G>A), located in coding exon 12 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1421. The arginine at codon 474 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple cohorts of individuals diagnosed with lymphoma, breast, colon and/or ovarian cancer (Havranek O et al. PLoS ONE. 2015 Oct;10:e0140819; Tung N et al. Cancer, 2015 Jan;121:25-33; Brovkina OI et al. Front Oncol. 2018 Oct 2;8:421; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439; Güleç Ceylan G et al. Tohoku J Exp Med, 2022 Nov;258:319-325). This variant was non-functional in an in vitro kinase assay and a human cell-based kinase assays measuring KAP1 phosphorylation and CHK2 autophosphorylation (Kleiblová P et al. Klin Onkol, 2019;32:36-50; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). In a mouse embryonic stem cell-based system, this alteration was found to be damaging to Kap1 phosphorylation (Boonen RACM et al. Cancer Res, 2022 02;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. -

Li-Fraumeni syndrome 2

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 03, 2023	Criteria applied: PS3,PM5,PS4_SUP -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 16, 2024

Variant summary: CHEK2 c.1421G>A (p.Arg474His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 233796 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.4e-05 vs 0.00031), allowing no conclusion about variant significance. c.1421G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer, or an unspecified hereditary cancer (e.g. Girard_2019, de Oliveira_2022, Kleiblova_2019, Couch_2015, Rizzolo_2019, Brovkina_2018, Bhai_2021, Akcay_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <20% of normal kinase activity (Kleiblova_2019, Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 34326862, 34903604, 30333958, 25452441, 30303537, 26506619, 31050813, 30613976, 30374176, 25186627, 35534704). ClinVar contains an entry for this variant (Variation ID: 126910). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

The CHEK2 c.1421G>A variant is predicted to result in the amino acid substitution p.Arg474His. This variant has been reported in an individual with non-Hodgkin lymphoma (Havranek et al. 2015. PubMed ID: 26506619), individuals with breast cancer (Couch et al. 2015. PubMed ID: 25452441, Table S6; Tung et al. 2015. PubMed ID: 25186627, Supp. Info; Girard et al. 2019. PubMed ID: 30303537, Table S3), and an individual with ovarian cancer (Kleiblova et al. 2019. PubMed ID: 31050813, Tables 1 and S3, Patient 1380). It has also been reported in an individual with a family history of hereditary breast and/or ovarian cancer (HBOC), but was also found in control individuals (Brovkina et al. 2018. PubMed ID: 30333958, Table 3, referred to as c.1550G>A, p.Arg517His). A variant interpretation study interpreted this variant as uncertain significance (Tsai et al. 2019. PubMed ID: 30374176, Table S1). Functional studies suggest this variant may impair CHK2 kinase catalytic activity (Kleiblova et al. 2019. PubMed ID: 31050813, Figure 2, Table S2). This variant has been reported at a frequency of ~0.02% in individuals of African origin in the gnomAD database. There are conflicting interpretations of pathogenicity ranging from likely pathogenic to likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126910/). Based on these observations, the c.1421G>A variant is classified as uncertain. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

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

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

4.8

H;.;H;.;H;.;H;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.6

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

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96

MVP

0.94

MPC

0.17

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Other links and lift over