22-28699866-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y327N) has been classified 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

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

CHEK2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
Li-Fraumeni syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

BS2

High AC in GnomAdExome4 at 26 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 9 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 9 of 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

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251474

AF XY:

0.0000221

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 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

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111876

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000998

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

Jul 09, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 28, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:6

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Sep 21, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Hereditary cancer-predisposing syndrome

Uncertain:3

Aug 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 10, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jan 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). 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 available evidence, the clinical significance of this variant remains unclear. -

Breast and/or ovarian cancer

Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

CHEK2-related disorder

Uncertain:1

Feb 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition

Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition

Uncertain:1

Jan 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.

PhyloP100

6.8

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

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over