22-28699866-T-C

Position:

chr22-28699866-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_007194.4(CHEK2):c.980A>G(p.Tyr327Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,830 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 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:18

Conservation

PhyloP100: 6.76

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 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.980A>G	p.Tyr327Cys	missense_variant	9/15	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.980A>G	p.Tyr327Cys	missense_variant	9/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251474

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135910

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2024	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); Observed in individuals with breast, bilateral breast, or prostate cancer, but also in unaffected controls (PMID: 34326862, 32832836, 29522266, 12533788, 30287823, 31409080, 33471991); Published functional studies are conflicting: reduced kinase activity, but DNA damage response and cell growth comparable to wild type (PMID: 30851065, 31050813); This variant is associated with the following publications: (PMID: 28201779, 12533788, 30287823, 30851065, 31050813, 32295079, 33471991, 19782031, 22419737, 32885271, 34326862, 32832836, 29522266, 31409080, 36243179) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 23, 2022	The frequency of this variant in the general population, 0.000026 (3/113756 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 31050813 (2019), 33471991 (2021), https://databases.lovd.nl/shared/variants/CHEK2), in an individual with prostate cancer (PMID: 12533788 (2003)), and in an individual with breast and thyroid cancer (PMID: 31050813 (2019)). The variant is also found in unaffected individuals (PMID: 30287823 (2018), 33471991 (2021), https://databases.lovd.nl/shared/variants/CHEK2). A functional study in human cells demonstrated that this variant had a damaging effect on protein (PMID: 31050813 (2019)), while a study on yeast found no effect (PMID: 30851065 (2019)). 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	Mayo Clinic Laboratories, Mayo Clinic	Jul 09, 2024	PM2 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial cancer of breast

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	This sequence change replaces tyrosine with cysteine at codon 327 of the CHEK2 protein (p.Tyr327Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs587780194, ExAC 0.006%). This variant has been observed in individuals affected with prostate cancer or breast cancer (PMID: 12533788, 31050813). ClinVar contains an entry for this variant (Variation ID: 128092) with 10 submitters all described it as of uncertain significance, two stars, no conflicts. In-silico predictions show pathogenic computational verdict based on 9 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MutationTaster, PrimateAI and SIFT vs 3 benign predictions from DEOGEN2, MVP and MutationAssessor.. The clinical significance of these results is unknown. Therefore, it has been classified as a Variant of Uncertain -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 21, 2020	- -
Uncertain significance, 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 cysteine, which is neutral and slightly polar, at codon 327 of the CHEK2 protein (p.Tyr327Cys). This variant is present in population databases (rs587780194, gnomAD 0.003%). This missense change has been observed in individual(s) with prostate cancer or breast cancer (PMID: 12533788, 31050813, 34326862). ClinVar contains an entry for this variant (Variation ID: 128092). 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, 31050813). 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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CHEK2 p.Tyr327Cys variant was identified in 1 of 800 proband chromosomes (frequency: 0.001) from an individual with sporadic prostate cancer and was not identified in 846 control chromosomes from healthy individuals or from 596 chromosomes from familial prostate cancer (Dong 2003). The variant was also identified in dbSNP (ID: rs587780194) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Gene Dx, Ambry Genetics, Counsyl, Invitae, Color and Fulgent Genetics). The variant was identified in control databases in 5 of 277198 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 3 of 126694 chromosomes (freq: 0.00002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Tyr327 residue is conserved in mammals but not in more distantly related 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2022	The p.Y327C variant (also known as c.980A>G), located in coding exon 8 of the CHEK2 gene, results from an A to G substitution at nucleotide position 980. The tyrosine at codon 327 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals diagnosed with prostate cancer (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also detected in 3/5589 German BRCA1/2-negative probands diagnosed with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Results from functional analyses of this variant are conflicting (Delimitsou A et al. Hum Mutat. 2019 May;40(5):631-648; Kleiblova P et al. Int J Cancer. 2019 Oct 1;145(7):1782-1797). 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	curation	Sema4, Sema4	Mar 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 01, 2023	This missense variant replaces tyrosine with cysteine at codon 327 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional impact of this variant on CHEK2 function is not clear, as one study in yeast has shown a neutral effect (PMID: 30851065), while another study in human cells reported a damaging effect (PMID: 31050813). This variant has been reported in an individual affected with breast cancer (PMID: 31050813) and in an individual affected with prostate cancer (PMID: 12533788). In a large case-control study, this variant has been observed in 5/60461 individuals affected with breast cancer and 5/53456 controls (OR=0.884, 95%CI 0.256 to 3.054; PMID: 33471991). This variant has been identified in 4/251474 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. -

Breast and/or ovarian cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2024

The CHEK2 c.980A>G variant is predicted to result in the amino acid substitution p.Tyr327Cys. This variant has been reported in individuals with prostate cancer (Dong et al. 2003. PubMed ID: 12533788), breast cancer (Kleiblova et al. 2019. PubMed ID: 31050813; Table S4, Bhai et al. 2021. PubMed ID: 34326862), and in a control individual from a breast cancer study (Momozawa et al. 2018. PubMed ID: 30287823). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is listed in ClinVar as uncertain by several diagnostic labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/128092/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast;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

May 23, 2017

- -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

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

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.85

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

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.5

L;L;L;.;L;.;L;.;L;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.0070

D;T;D;.;D;D;.;T;T;D;.;.

Polyphen

1.0

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

Vest4

0.85

MVP

0.72

MPC

0.17

ClinPred

0.94

GERP RS

5.7

Varity_R

0.79

gMVP

0.79

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