rs1060502688

Positions:

chr22-28725260-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_007194.4(CHEK2):c.427C>T(p.His143Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,972 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. H143?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6

Conservation

PhyloP100: 7.60

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_007194.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-28725258-GTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1739257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

PP5

Variant 22-28725260-G-A is Pathogenic according to our data. Variant chr22-28725260-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410008.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.427C>T	p.His143Tyr	missense_variant	3/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.427C>T	p.His143Tyr	missense_variant	3/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 02, 2023	The p.H143Y variant (also known as c.427C>T), located in coding exon 2 of the CHEK2 gene, results from a C to T substitution at nucleotide position 427. The histidine at codon 143 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in an early-onset breast cancer cohort and results in an unstable CHK2 protein (Bell DW et al. Int. J. Cancer. 2007 Dec;121:2661-7). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). In one study, this alteration was identified in an individual diagnosed with ovarian cancer (Song H et al. J Med Genet, 2021 05;58:305-313). This alteration was reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). Based on internal structural analysis this variant is anticipated to impact a residue that is important for protein function (Cai Z et al. Mol. Cell. 2009 Sep;35:818-29; 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2023	This missense variant replaces histidine with tyrosine at codon 143 of the CHEK2 protein. Computational prediction tool 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 demonstrated the mutant protein to be unstable and expressed at reduced levels (PMID: 17721994, 31780696). The mutant protein has also been shown to lack the ability to autophosphorylate (PMID: 31780696) and is less associated with BRCA1 (PMID: 33986034). This variant has been reported in an individual affected with early-onset breast cancer, who also carried an unspecified BRCA1 mutation (PMID: 17721994), and in an individual affected with ovarian cancer (PMID: 32546565). This variant has been identified in 2/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a woman age 70 years or older without cancer (https://whi.color.com/variant/22-29121248-G-A). Although functional studies indicate that this variant may have deleterious impact on CHEK2 function, the available clinical 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 provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2023	In the published literature, this variant has been reported in individuals with breast or ovarian cancer (PMIDs: 34326862 (2021), 32546565 (2021), 17721994 (2007)), as well as in an unaffected control individual (PMID: 30303537 (2019)) and in one individual in a cohort of healthy older women (FLOSSIES (https://whi.color.com/)). Experimental studies have shown this variant has deleterious effects on CHEK2 protein expression and kinase activity (PMIDs: 31780696 (2019), 17721994 (2007)). The frequency of this variant in the general population, 0.000064 (2/31396 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	GeneDx	Aug 09, 2023	Published functional studies are inconclusive: conflicting results on protein stability, reduced kinase activity, and diminished co-localization with BRCA1 (Bell et al., 2007; Dutil et al., 2019; Bazinet et al., 2021); 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: 10694887, 19522503, 33986034, 31780696, 17721994, 27842325, 19782031, 22419737, 34326862, 30303537, 32832836, 32546565) -

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 11, 2023

PS3, PM2_sup, PP3_sup. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Boonen et al. 2022 und Stolarova et al. 2023 impaired function, PM2 (supporting pathogenic): Absent from NFE in gnomAD, PP3 (supporting pathogenic): In silico prediction mainly damaging -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 29, 2022

Variant summary: CHEK2 c.427C>T (p.His143Tyr) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain(IPR000253) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 257116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.427C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (Bell_2007). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Functional analysis of the variant has shown that the variant encodes a grossly unstable protein (Bell_2007), loses the ability to auto-phosphorylate at Serine 516 and to be phosphorylated by ATM at Threonine 68 (Dutil_2019), and drastically impairs CHK2 association to BRCA1, suggesting that it significantly disrupts the FHA domain (Bazinet_2021). However, additional functional studies are needed to determine the role of this variant in disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. It was classified as VUS (n=4) and Likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -

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

Jul 18, 2022

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2023

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 143 of the CHEK2 protein (p.His143Tyr). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with breast, uterine, and thyroid cancers (PMID: 17721994, 34326862). ClinVar contains an entry for this variant (Variation ID: 410008). 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: 17721994, 31780696, 33986034). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.4

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

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.73

MVP

0.99

MPC

0.17

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.85

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