22-28695800-T-C

Position:

chr22-28695800-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_007194.4(CHEK2):c.1169A>G(p.Tyr390Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,294 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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 6.94

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 22-28695800-T-C is Pathogenic according to our data. Variant chr22-28695800-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410015.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=4}. Variant chr22-28695800-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1169A>G	p.Tyr390Cys	missense_variant	11/15	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.1169A>G	p.Tyr390Cys	missense_variant	11/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461108

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726910

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 28, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25619829, 29761796]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 390 of the CHEK2 protein (p.Tyr390Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer and healthy controls (PMID: 25619829, 31871109, 32959997, 34991090). This variant is also known as c.1298A>G (p.Tyr433Cys). ClinVar contains an entry for this variant (Variation ID: 410015). 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: 25619829). This variant disrupts the p.Tyr390 amino acid residue in CHEK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22114986, 25503501, 27553368, 27751358, 30441849, 30613976, 32957588, 33919281, 33925588; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 21, 2022	- -

not provided

Uncertain:3

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The p.Y390C variant (also known as c.1169A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1169. The tyrosine at codon 390 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also detected in 3/95 Turkish women with breast or ovarian cancer who were diagnosed before 50 years of age and known to not carry mutations in the BRCA1, BRCA2, and PALB2 genes and in 1/60 controls without breast cancer and without a family history of breast cancer (Aksoy F et al. Hum Hered, 2022 Jan). This alteration occurs at a statistically increased frequency in Chinese breast cancer patients compared to an ethnically- and age-matched control population (Wang N et al. Oncogene, 2015 Oct;34:5198-205). This variant is unable to efficiently phosphorylate p53 and CDC25A and CHEK2-knockdown cells rescued with this variant also show weaker expression of p53 transcriptional targets. These defects may directly contribute to the observed inability of this variant to restore sensitivity to DNA damaging agents; increased cell survival; decreased rates of apoptosis; and deregulation of the cell cycle after DNA damage, each of which were similar to cells which had CHEK2-knockdown in contrast to cells rescued with wildtype CHEK2 (Wang N et al. Oncogene, 2015 Oct;34:5198-205; Luo L et al. Med. Sci. Monit., 2018 May;24:3176-3183). 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). Based on internal structural assessment, this alteration disrupts a highly conserved motif in kinases that is necessary for positioning the activation loop (Lountos GT et al. J. Struct. Biol., 2011 Dec;176:292-301; Moore MJ et al. J. Biol. Chem., 2003 Mar;278:10613-8; Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Oct 12, 2023

Located in Kinase domain, Loss of function in both assays applied by Stolarova et al. as well as in Boonen et al. 2022,PS3, Prediction deleterious PP3_sup, not in gnomAD PM2_sup. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Loss of function in Stolarova et al. 2023, Boonen et al. 2021 and Wang et al. 2015, PM2 (supporting pathogenic): Not in gnomAD, PP3 (supporting pathogenic): In silico prediction deleterious -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 09, 2023

Variant summary: CHEK2 c.1169A>G (p.Tyr390Cys) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251046 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1169A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and in multiple case control studies was reported at a higher frequency in cases than controls (Wang_2015, Aksoy_2022, Adedokun_2020), however these reports do not show strong evidence for causality (segregation data,etc). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least three publications have reported experimental evidence evaluating an impact on protein function, finding that cells expressing the variant of interest display reduced sensitivity to DNA-damaging agents as well as impaired p53 activitation, cell cycle arrest, and apoptosis upon DNA damage as well as reduced kinase activity toward Kap1; cells expressing the CHEK2 Y390C variant behaved similarly to CHEK2-null cells expressing an empty-vector control (e.g., Wang_2015, Luo_2018, Boonen_2022). Additionally, a different variant affecting the same codon has been reported as pathogenic by our lab (p.Tyr390Ser). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;T;.;T;.;T;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.95

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

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.1

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

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-8.7

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

REVEL

Pathogenic

0.88

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

0.99

MVP

0.91

MPC

0.17

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.92

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

Other links and lift over