rs878854908

Variant names:

• chr22-28696953-A-C
• rs878854908
• NM_007194.4:c.1043T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-28696953-A-C
• chr22-28696953-A-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007194.4(CHEK2):​c.1043T>G​(p.Leu348*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHEK2 NM_007194.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.31
• Publications: 3 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-28696953-A-C is Pathogenic according to our data. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28696953-A-C is described in CliVar as Pathogenic. Clinvar id is 921230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1043T>G	p.Leu348*	stop_gained	Exon 10 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1043T>G	p.Leu348*	stop_gained	Exon 10 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Apr 07, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L348* pathogenic mutation (also known as c.1043T>G), located in coding exon 9 of the CHEK2 gene, results from a T to G substitution at nucleotide position 1043. This changes the amino acid from a leucine to a stop codon within coding exon 9. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Dec 13, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 10 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast Pathogenic:2

Jun 27, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu348*) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 921230). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.3
Vest4		0.96
GERP RS		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs878854908; hg19: chr22-29092941;