22-28734546-G-T

Position:

chr22-28734546-G-T

Variant summary

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

The NM_007194.4(CHEK2):c.176C>A(p.Thr59Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 6.35

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.176C>A	p.Thr59Lys	missense_variant	2/15	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.176C>A	p.Thr59Lys	missense_variant	2/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152004

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251456

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727248

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:

0.0000513

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74234

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000414

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2023	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; Published functional study demonstrates reduction of DNA damage repair (PMID: 22419737); Observed in individuals with breast, colon, stomach, or ovarian cancer (PMID: 12052256); This variant is associated with the following publications: (PMID: 15492928, 12610780, 23296741, 15385111, 16551709, 26506619, 16078115, 21807500, 15122511, 25467110, 18004398, 22058428, 21876083, 11719428, 28492532, 26206375, 14569133, 14568168, 16080966, 22114986, 11733767, 22419737, 12052256) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2024	The CHEK2 c.176C>A (p.Thr59Lys) variant has been reported in the published literature in individuals with breast cancer (PMID: 28779002 (2017), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)) and in cohort of individuals with breast, colorectal, stomach, or ovarian cancer (PMID: 12052256 (2002)). This variant has also been identified in reportedly healthy individuals (PMID: 28779002 (2017), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A yeast based functional study reported that this variant displays an intermediate response to DNA damage (PMID: 22419737 (2012)). The frequency of this variant in the general population, 0.000035 (4/113734 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 26, 2015	Variant summary: This c.176C>A variant affects a conserved nucleotide, resulting in non-conservative amino acid change from Thr to Lys. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/50644 control chromosomes for a frequency of 0.0000395, which slightly exceeds the maximal expected frequency of a pathogenic allele (0.0000284) in this gene based on the disease prevalence of LFS. However, there are only two variant occurrences and this may not rule out the chance finding. In addition, low frequency coupled with only two variant occurrences may also indicate that the variant carriers might represent as subclinical cases or reduced penetrance. This assumption is also supported by its occurrence in cancer patients. The variant has been reported in multiple cancer families with spectrum of cancers (familial and sporadic breast cancer, stomach cancer, thyroid cancer, colorectal cancer, ovarian cancer and prostate cancer) (Ingvarsson 2002). However, the available family data does not strongly indicate a positive or a lack of cosegregation with the disease. It is not specified in the publication whether the families with this variant fulfilled the diagnostic criteria for LFS. One yeast-based in vivo functional assay showed a decrease in DNA damage response by this variant; however, the finding was not sufficient to strongly infer the pathogenicity. LOH analysis in tumor samples was consistent with a possible pathogenic outcome. One clinical laboratory has classified this variant as having uncertain significance. Taken together, this variant has currently been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 02, 2024	PM2 -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	This missense variant replaces threonine with lysine at codon 59 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). A yeast-based complementation assay has shown that this variant protein partially impacts DNA damage response compared with wild-type protein (PMID: 22419737). This variant has been reported in individuals affected with breast, colorectal, stomach, and ovarian cancer (PMID: 12052256). This variant has also been identified in 4/251456 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2024	The p.T59K variant (also known as c.176C>A), located in coding exon 1 of the CHEK2 gene, results from a C to A substitution at nucleotide position 176. The threonine at codon 59 is replaced by lysine, an amino acid with similar properties. In a large Icelandic study assessing breast tumors for loss of heterozygosity at the CHEK2 gene locus, this alteration was identified as a germline mutation in 9 individuals with cancer across 5 families, including individuals with breast, colon, ovarian, stomach, gastric, prostate and thyroid cancer. Some of these individuals had multiple primary cancers, and the youngest breast cancer diagnosis was at age 29. In total, this alteration segregated with cancer in 9 of 11 individuals with cancer across these 5 families. This alteration was absent in six individuals without a history of cancer in one of these families, and it was absent in 452 control subjects. Authors concluded that this may be a low penetrance cancer susceptibility allele (Ingvarsson S et al. Breast Cancer Res. 2002;4:R4). Another research group subsequently developed a yeast-based assay to assess in vivo CHEK2- mediated response to DNA damage and determined that this allele had an intermediate or partial loss of DNA damage response compared to that mediated by wild-type CHEK2 alleles (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). In addition, this alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2022	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 59 of the CHEK2 protein (p.Thr59Lys). This variant is present in population databases (rs149991239, gnomAD 0.004%). This missense change has been observed in individual(s) with breast, ovarian and colorectal cancer (PMID: 12052256). ClinVar contains an entry for this variant (Variation ID: 142041). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 22419737). 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, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 06, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

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

Oct 31, 2018

- -

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

May 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

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

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.72

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

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.4

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

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.51

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.0040

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

Polyphen

1.0

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

Vest4

0.67

MVP

0.98

MPC

0.17

ClinPred

0.85

GERP RS

5.4

Varity_R

0.48

gMVP

0.56

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