22-28689235-A-C

Variant names:

• chr22-28689235-A-C
• rs747767986
• NM_007194.4:c.1462-20T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_007194.4(CHEK2):​c.1462-20T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.280
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-28689235-A-C is Benign according to our data. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-28689235-A-C is described in CliVar as Likely_benign. Clinvar id is 518216.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1462-20T>G		intron_variant	Intron 13 of 14	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1462-20T>G		intron_variant	Intron 13 of 14	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 19, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.51
PhyloP100		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747767986; hg19: chr22-29085223;