rs121908703

Positions:

Variant summary

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

The NM_007194.4(CHEK2):c.1067C>T(p.Ser356Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S356P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15O:1

Conservation

PhyloP100: 7.84

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1067C>T	p.Ser356Leu	missense_variant	10/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1067C>T	p.Ser356Leu	missense_variant	10/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.0000159

AC:

AN:

251254

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135816

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:

0.00000411

AC:

AN:

1460648

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

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

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4Other:1

not provided, no classification provided	literature only	Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2024	Published functional studies demonstrate DNA damage response comparable to wild type in a yeast-based assay as well as normal Chk2-autophosphorylation but intermediate/reduced kinase activity against KAP1 in human-cell based studies (PMID: 30851065, 31050813, 37449874); Observed in individuals with a personal and/or family history of breast and other cancers, but also observed in controls (PMID: 29700698, 30303537, 31050813, 34991090, 36315097); 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: 26506619, 29700698, 34426522, 31050813, 30303537, 34991090, 34565017, 30851065, 37449874, 36315097, 19782031, 22419737) -
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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -

Familial cancer of breast

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 08, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 356 of the CHEK2 protein (p.Ser356Leu). This variant is present in population databases (rs121908703, gnomAD 0.004%). This missense change has been observed in individual(s) with non-Hodgkin lymphoma, thyroid cancer, or breast cancer (PMID: 26506619, 29700698, 30303537). ClinVar contains an entry for this variant (Variation ID: 126907). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31050813, 31409080). 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	Dec 12, 2023	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 26, 2017	Variant summary: The CHEK2 c.1067C>T (p.Ser356Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/215270 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000036 (4/111556). This frequency is about 1.3 times the estimated maximal expected allele frequency of an LFS-causing CHEK2 variant (0.0000284), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, there are no other supporting evidences. This variant has been reported in one patient with non-Hodgkin Lymphoma (Havranek_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as Variant of Unknown Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 26, 2023	The p.S356L variant (also known as c.1067C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1067. The serine at codon 356 is replaced by leucine, an amino acid with dissimilar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This alteration was identified in an individual diagnosed with breast and/or ovarian cancer (Aksoy F et al. Hum Hered, 2022 Jan;:). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 14, 2022	This missense variant replaces serine with leucine at codon 356 of the CHEK2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Functional studies have provide inconclusive results regarding this variant. The variant did not show functional deficit in a yeast DNA repair assay (PMID 30851065) but demonstrated intermediate functional impact in a kinase assay (PMID 31050813). This variant has been reported in 2 individuals with breast cancer (PMID: 30303537), an individual affected with non-Hodgkin lymphoma (PMID 26506619), and a patient with thyroid carcinoma (PMID 29700698) in the literature. This variant has been identified in 4/251254 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. -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The CHEK2 c.1067C>T variant is predicted to result in the amino acid substitution p.Ser356Leu. This variant has been reported as a germline variant in an individual with Non-Hodgkin lymphoma (NHL) (Havranek et al. 2015. PubMed ID: 26506619) and in individuals with familial breast cancer (Supplementary Table S3, Girard et al. 2018. PubMed ID: 30303537). This variant has also been reported in the control population in an study of individuals with breast and ovarian cancer (Table 1, Kleiblova et al. 2019. PubMed ID: 31050813). A study analyzing in silico prediction tools and a yeast functional assay reported conflicting results for this variant, with in silico suggesting it is possibly damaging and in vivo results finding it benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted with uncertain significance in ClinVar by several outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/126907/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of prostate

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Sep 06, 2021

- -

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.Ser356Leu variant was identified in 1 of 680 proband chromosomes (frequency: 0.002) from individuals or families with Non-Hodgkin Lymphoma and was not identified in 890 control chromosomes from healthy individuals (Havranek 2015). The variant was also identified in dbSNP (ID: rs121908703) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by Ambry Geneics, Invitae, Color Genomics), Cosmic (1x in urinary tract tumor), and in MutDB. The variant was not identified in Zhejiang University database. The variant was identified in control databases in 4 of 246052 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 4 of 111556 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser356 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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, HumanSpliceFinder) 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

Benign

0.19

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.50

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

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.5

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.0

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

REVEL

Benign

0.21

Sift

Benign

0.034

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

Sift4G

Benign

0.11

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

Polyphen

0.97

D;D;.;D;P;D;D;.;.

Vest4

0.78

MutPred

0.61

Loss of disorder (P = 0.0204);Loss of disorder (P = 0.0204);.;Loss of disorder (P = 0.0204);.;Loss of disorder (P = 0.0204);.;.;.;

MVP

0.68

MPC

0.13

ClinPred

0.81

GERP RS

5.7

Varity_R

0.43

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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