chr22-28689235-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_007194.4(CHEK2):​c.1462-20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,417,290 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-28689235-A-G is Benign according to our data. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28689235-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 371987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 23 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD2 exomes AF: 0.0000300 AC: 7 AN: 233050 AF XY: 0.0000390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 23 AN: 1265048 Hom.: 0 Cov.: 18 AF XY: 0.0000156 AC XY: 10 AN XY: 639146

African (AFR) AF: 0.00 AC: 0 AN: 29688

American (AMR) AF: 0.0000899 AC: 4 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24972

East Asian (EAS) AF: 0.00 AC: 0 AN: 38860

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37850

Middle Eastern (MID) AF: 0.000263 AC: 1 AN: 3796

European-Non Finnish (NFE) AF: 0.0000148 AC: 14 AN: 948450

Other (OTH) AF: 0.0000552 AC: 3 AN: 54308

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:3

Mar 08, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome Benign:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 28, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.91
DANN	Benign	0.51
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs747767986; hg19: chr22-29085223;