chr22-28695800-T-G

Position:

chr22-28695800-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_007194.4(CHEK2):c.1169A>C(p.Tyr390Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000013 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y390C) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:2

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_007194.4

PM5

Other missense variant is known to change same aminoacid residue: 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: {Likely_pathogenic=4, Uncertain_significance=2}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 22-28695800-T-G is Pathogenic according to our data. Variant chr22-28695800-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1169A>C	p.Tyr390Ser	missense_variant	11/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1169A>C	p.Tyr390Ser	missense_variant	11/15	1	NM_007194.4	P2	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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251046

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135710

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:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461108

Hom.:

Cov.:

AF XY:

0.0000165

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

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:

0.00000378

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:4Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Mar 13, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PS3, PS4_STR -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
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: 34903604, 22114986, 25619829, 29761796]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 390 of the CHEK2 protein (p.Tyr390Ser). This variant is present in population databases (rs200928781, gnomAD 0.005%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer, colorectal cancer, ovarian cancer, and/or uterine sarcoma (PMID: 22114986, 25503501, 27553368, 27751358, 30441849, 30613976, 32957588, 33919281, 33925588, 35220195; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1298A>C, p.Tyr433Ser. ClinVar contains an entry for this variant (Variation ID: 141818). 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: 22114986, 30851065, 34903604). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 04, 2023	This missense variant replaces tyrosine with serine at codon 390 of the CHEK2 protein. 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 shown that this variant was damaging in kinase assays in mouse embryonic stem cells and in vitro (PMID: 22114986, 34903604) and in a yeast DNA damage repair assay (PMID: 30851065). This variant has been reported in at least six individuals affected with breast cancer (PMID: 22114986, 25503501, 33919281, 33925588, 34072659; DOI:10.14744/ejmo.2022.88057) and in a breast cancer case-control meta-analysis in 3/60463 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000348). This variant also has been reported in one individual each affected with ovarian, pancreatic and Mullerian sarcoma in the uterus (PMID: 29922827, 30441849, 32957588). This variant has been identified in 6/251046 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 2023	The p.Y390S variant (also known as c.1169A>C), located in coding exon 10 of the CHEK2 gene, results from an A to C substitution at nucleotide position 1169. The tyrosine at codon 390 is replaced by serine, an amino acid with dissimilar properties. This alteration is located in the kinase domain of the CHK2 protein. Based on an in vitro kinase activity test combined with in silico models, this alteration had been associated with no detectable kinase activity and was interpreted as probably deleterious (Desrichard A et al. Breast Cancer Res. 2011;13(6):R119). This alteration also behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 May;40:631-648) and was reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 02;82:615-631). This alteration has been reported in multiple patients undergoing multi-gene panel testing, including individuals diagnosed with breast and/or ovarian cancer (Leedom TP et al. Cancer Genet. 2016 Sep;209(9):403-407; Pinto P et al. Breast Cancer Res Treat. 2016 Sep;159(2):245-56; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Koczkowska M et al. Cancers (Basel), 2018 Nov;10; Solano AR et al. Cancers (Basel), 2021 May;13; Apostolou P et al. Cancers (Basel), 2021 Apr;13:). 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. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 08, 2021	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Published functional studies demonstrate a damaging effect: loss of kinase activity and DNA-damage response (PMID: 22114986, 30851065, 34903604, 37449874); Observed in individuals with personal and/or family history of CHEK2-related cancers (PMID: 22114986, 25503501, 27553368, 32957588, 35220195, 36360192, 37694493); 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: 22114986, 25503501, 27751358, 28152038, 27553368, 30441849, 30851065, 29922827, 34903604, 32183364, 34480478, 33471991, 33925588, 30613976, 33919281, 32805687, 32957588, 35220195, Ayaz2022[article], 19782031, 37694493, 36360192, 37449874) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 30, 2023	In the published literature, this variant has been reported in individuals affected with breast cancer or ovarian cancer, and in individuals at increased risk for cancer based on family history (PMIDs: 22114986 (2011), 27553368 (2016), 27751358 (2016), 30441849 (2018), 32957588 (2020), 33919281 (2021), and 33925588 (2021)). In addition, experimental studies indicate this variant is damaging to CHEK2 protein function (PMIDs: 34903604 (2021), 30851065 (2019), 22114986 (2011), 20713355 (2010)). 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, this variant is classified as likely pathogenic. -

Li-Fraumeni syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Dec 11, 2023

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 390 of the CHEK2 protein (p.Tyr390Ser). This variant is present in population databases (rs200928781, gnomAD 0.005%). This variant is also called c.1298A>C (p.Tyr433Ser; NM_001005735.2) This missense change has been observed in individual(s) with a personal and/or family history of breast cancer, colorectal cancer, ovarian cancer, and/or uterine sarcoma (PMID: 22114986, 25503501, 27751358, 28152038, 27553368, 30441849, 30851065, 29922827, 19782031, 34903604, 32183364, 34480478, 33471991, 33925588, 30613976, 33919281, 32805687, 32957588, 35220195). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141818). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect: loss of kinase activity and DNA-damage response (Desrichard et al., 2011; Delimitsou et al., 2019; Boonen et al., 2022). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Malignant tumor of prostate

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Oct 18, 2021

- -

Premature ovarian failure

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano

Mar 02, 2020

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 01, 2023

Variant summary: CHEK2 c.1169A>C (p.Tyr390Ser) results in a non-conservative amino acid change to a highly conserved residue (HGMD) 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 allele was found at a frequency of 2.4e-05 in 252072 control chromosomes (gnomAD). c.1169A>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or Prostate Cancer (e.g. Maxwell_2014, Koczkowska_2018, Apostolou_2021, Kirchner_2022). These data indicate that the variant is very likely to be associated with disease. In functional assays (in vitro kinase activity assay and yeast based functional assay), the variant of interest was found to have activity similar to the negative control and the well-characterized 1100delC mutation (Desrichard_2011, Delimitsou_2019). In a mouse embryonic stem cell-based system, the variant protein showed a similar extent of impairment of Kap1 phosphorylation as truncating variants (Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25503501, 27553368, 22114986, 27751358, 29922827, 30851065, 30441849, 32183364, 33925588, 32090079, 36360192, 35643632). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=10) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CHEK2 p.Tyr390Ser variant was identified in 6 of 93488 proband chromosomes (frequency: 0.00006) from individuals or families with breast cancer and was not identified in 1026 control chromosomes from healthy individuals (Desrichard 2011, Leedom 2016, Maxwell 2015, Pinto 2016). The variant was also identified in dbSNP (ID: rs200928781) as "With Likely pathogenic, Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae and Counsyl; as likely pathogenic by Ambry Genetics, GeneDx and Color). The variant was identified in control databases in 6 of 245894 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 6 of 111380 chromosomes (freq: 0.00005); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was found disrupt CHEK2 kinase activity through an in vitro kinase activity assay (Desrichard 2011). The p.Tyr390 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

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

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.5

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-8.7

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

0.99

MutPred

0.91

Gain of disorder (P = 0.0882);.;Gain of disorder (P = 0.0882);.;Gain of disorder (P = 0.0882);.;Gain of disorder (P = 0.0882);.;.;

MVP

0.90

MPC

0.18

ClinPred

0.99

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.93

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