22-28725265-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_007194.4(CHEK2):​c.422A>C​(p.Lys141Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,824 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: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:11

Conservation

PhyloP100: 6.12
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_007194.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.422A>C p.Lys141Thr missense_variant Exon 3 of 15 ENST00000404276.6 NP_009125.1 O96017-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHEK2ENST00000404276.6 linkc.422A>C p.Lys141Thr missense_variant Exon 3 of 15 1 NM_007194.4 ENSP00000385747.1 O96017-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461824
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727214
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Pathogenic:1Uncertain:4
Apr 08, 2020
Center of Medical Genetics and Primary Health Care
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

ACMG Guidelines 2015 criteria This variant is in exon 3 of the CHEK2 gene in the forkhead-associated (FHA) domain (aa 113-175); it functions as a phosphopeptide recognition domain found in many regulatory proteins. It is in a mutation hotspot of 16 pathogenic variants (source ClinVar) (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 26976419, 27616075). 12 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL, SIFT, PolyPhen-2 and Align-GVGD versus 1 benign prediction from PrimateAI support its deleterious effect (PP3 Pathogenic Supporting). In our study this variant was found in a 45-year-old female with unilateral breast cancer and a strong family history. This patient also had a VUS in the SLX4 gene. Although this variant has been reported in ClinVar as a VUS, based on the evidence provided above, we classified this variant as a Likely Pathogenic. -

Mar 08, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 141 of the CHEK2 protein (p.Lys141Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 26976419, 27616075, 33558524, 33980423). ClinVar contains an entry for this variant (Variation ID: 186751). 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 does not substantially affect CHEK2 function (PMID: 37449874). 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. -

Apr 12, 2018
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 20, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:3
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 07, 2018
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is denoted CHEK2 c.422A>C at the cDNA level, p.Lys141Thr (K141T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant was observed in at least three individuals with breast cancer (Tung 2015, Tung 2016, Kraus 2017). CHEK2 Lys141Thr was not observed in large population cohorts (Lek 2016). This variant is located in the FHA domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Lys141Thr is a pathogenic or benign variant. We consider it to be 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.Lys141Thr variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with stage I to stage III breast cancer (Tung 2016). The variant was also identified in dbSNP (ID: rs786203192) as “with uncertain significance allele” and in the ClinVar and Clinvitae databases as uncertain significance by Ambry Genetics, GeneDx and Invitae. The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Lys141 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 Thr 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

Hereditary cancer-predisposing syndrome Uncertain:2
Mar 04, 2025
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces lysine with threonine at codon 141 in the FHA domain of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. One functional study has shown this variant to have intermediate impact on CHEK2 auto-phosphorylation and phosphorylation of CHEK2 substrate KAP1 in a mouse embryonic stem cell based assay (PMID: 34903604), while another similar kinase activity study in a CHEK2-deficient human cell based assay has shown this variant to have no significant impact on kinase activity (PMID: 37449874). This variant has been reported in at least four individuals affected with breast cancer (PMID: 26976419, 27616075, 25186627, 33558524, 33980423). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant has shown an inconclusive association with breast cancer (4/60466 cases and 0/53461 controls; p-value=0.128) (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may have a pathogenic role, the available functional evidence is conflicting, and clinical evidence is insufficient to determine the association of this variant with breast cancer conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 18, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.K141T variant (also known as c.422A>C), located in coding exon 2 of the CHEK2 gene, results from an A to C substitution at nucleotide position 422. The lysine at codon 141 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in individuals with personal and/or family histories of breast cancer (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Kraus C et al. Int J Cancer, 2017 Jan;140:95-102; Hauke J et al. Cancer Med. 2018 Apr;7:1349-1358; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9; Güleç Ceylan G et al. Tohoku J Exp Med, 2022 Nov;258:319-325). This alteration was reported as intermediate in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631). 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. -

not specified Uncertain:1
Sep 03, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CHEK2 c.422A>C (p.Lys141Thr) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant has been found at a frequency of 3.1e-06 in control population (gnomAD). c.422A>C has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer Syndrome (Kraus_2017, Moradian_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an intermediate effect (43% reduction) on phosphorylation of its substrate Kap1 in a mouse embryonic stem (mES) cellbased system (Boonen_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34903604, 27616075, 33558524). ClinVar contains an entry for this variant (Variation ID: 186751). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:Li-Fraumeni syndrome 2 Uncertain:1
Jan 19, 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
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;.;D;D;.;D;.;.;.;D;.;T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.97
.;D;.;.;D;D;.;D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Uncertain
2.3
M;M;M;M;.;M;M;.;.;.;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-4.4
D;D;D;D;D;.;D;D;D;.;.;N
REVEL
Pathogenic
0.74
Sift
Benign
0.042
D;D;D;D;D;.;D;D;D;.;.;T
Sift4G
Uncertain
0.050
T;T;T;T;D;.;T;T;D;D;.;.
Polyphen
0.94
P;P;P;P;D;P;P;.;.;.;.;.
Vest4
0.63
MutPred
0.52
Gain of phosphorylation at K141 (P = 0.0351);Gain of phosphorylation at K141 (P = 0.0351);Gain of phosphorylation at K141 (P = 0.0351);Gain of phosphorylation at K141 (P = 0.0351);.;Gain of phosphorylation at K141 (P = 0.0351);Gain of phosphorylation at K141 (P = 0.0351);Gain of phosphorylation at K141 (P = 0.0351);.;Gain of phosphorylation at K141 (P = 0.0351);Gain of phosphorylation at K141 (P = 0.0351);Gain of phosphorylation at K141 (P = 0.0351);
MVP
0.97
MPC
0.15
ClinPred
0.98
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.71

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.

Other links and lift over

dbSNP: rs786203192; hg19: chr22-29121253; API