rs779269031
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_007194.4(CHEK2):c.275C>T(p.Pro92Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P92H) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 4.55
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.41632676).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.275C>T | p.Pro92Leu | missense_variant | 2/15 | ENST00000404276.6 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.275C>T | p.Pro92Leu | missense_variant | 2/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251294Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135836
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461806Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727196
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GnomAD4 genome
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31
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2023 | The p.P92L variant (also known as c.275C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 275. The proline at codon 92 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). This variant was also observed in 2/3251 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). This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Jul;:OF1-OF14). This amino acid position is well 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 | Apr 30, 2019 | - - |
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.Pro92Leu variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with stage I to III breast cancer and was listed as uncertain significance in this study (Tung 2016). The variant was also identified in dbSNP (ID: rs779269031) as “With Uncertain significance”, ClinVar (1x, as uncertain significance, by Invitae), Clinvitae (1x as uncertain significance), Cosmic (reported 2x, in skin with malignant melanoma and carcinoma). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 4 of 246194 chromosomes at a frequency of 0.000016 (Genome Aggregation Consortium Feb 27, 2017)". In addition the p.Pro92 variant was identified with a different substitution and amino acid consequence (c.275C>G, p.Pro329Arg), in the literature in a cohort of BRCA1/2-negative early-onset and familial breast and/or ovarian cancer patients from Pakistan, as potentially deleterious (Rashid 2013). The p.Pro92Arg variant was not identified in control databases. The p.Pro92 residue is conserved across mammals and other 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 c.275C>T 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. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 27, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 92 of the CHEK2 protein (p.Pro92Leu). This variant is present in population databases (rs779269031, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 410059). 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 tolerated. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.;D;D;T;.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;N;N;D;.;.
REVEL
Uncertain
Sift
Benign
T;T;T;T;D;.;D;T;D;D;D;.;.
Sift4G
Benign
T;T;T;T;T;.;D;T;T;T;D;.;.
Polyphen
P;D;P;P;D;P;P;D;.;.;.;.;.
Vest4
MutPred
Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);Loss of glycosylation at P92 (P = 0.0086);
MVP
MPC
0.057
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at