rs555607708

Variant names:

• chr22-28695868-AG-A
• rs555607708
• NM_007194.4:c.1100delC

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PP5_Strong

The NM_007194.4(CHEK2):c.1100delC (p.Thr367MetfsTer15) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00172 (AC=262) in the gnomAD database across 152,324 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00188. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.67). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915968: Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_007194.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:95 U:1 O:2
• Conservation: PhyloP100: 8.67
• Publications: 1 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, ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 11 of 15) at amino acid 367 of 543, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~380 amino acids (163 amino acids lost).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000915968: Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant.; SCV000187220: This alteration is reported to abolish the kinase activity of CHK2 (Wu X et al. J. Biol. Chem. 2001 Jan;276(4):2971-4).; SCV003933671: assay reports loss of kinase activity in functional studies. PMID:11053450; SCV006052446: Experimental studies have shown lack of kinase activity (PMID: 16982735, PMID: 31050813, PMID: 11719428, PMID: 11053450, PMID: 22114986), low protein expression and protein stability (PMID: 16982735) (PS3).; SCV000149889: Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); SCV000603087: "Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001)."; SCV002070848: "In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450)."; SCV000698761: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012).; SCV001549046: Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001).; SCV000806862: Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (95/96 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CHEK2 NM_007194.4	MANE Select	c.1100delC p.Thr367MetfsTer15	frameshift	Exon 11 of 15	Prot: NP_009125.1 UniProt:
	CHEK2 NM_001005735.3		c.1229delC p.Thr410MetfsTer15	frameshift	Exon 12 of 16	Prot: NP_001005735.1 UniProt:
	CHEK2 NM_001438293.1		c.1193delC p.Thr398MetfsTer15	frameshift	Exon 12 of 16	Prot: NP_001425222.1

CHEK2 NM_007194.4

MANE Select

HGVSc / HGVSpc.1100delCp.Thr367MetfsTer15

Exon rankExon 11 of 15

frameshift

Prot: NP_009125.1UniProt: O96017-1

CHEK2 NM_001005735.3

HGVSc / HGVSpc.1229delCp.Thr410MetfsTer15

Exon rankExon 12 of 16

frameshift

Prot: NP_001005735.1UniProt: O96017-9

CHEK2 NM_001438293.1

HGVSc / HGVSpc.1193delCp.Thr398MetfsTer15

Exon rankExon 12 of 16

frameshift

Prot: NP_001425222.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CHEK2 ENST00000404276.6	TSL:1MANE Select	c.1100delC p.Thr367MetfsTer15	frameshift	Exon 11 of 15	Prot: ENSP00000385747.1 UniProt:
	CHEK2 ENST00000382580.6	TSL:1	c.1229delC p.Thr410MetfsTer15	frameshift	Exon 12 of 16	Prot: ENSP00000372023.2 UniProt:
	CHEK2 ENST00000402731.6	TSL:1	c.899delC p.Thr300MetfsTer15	frameshift	Exon 9 of 13	Prot: ENSP00000384835.2 UniProt:

CHEK2 ENST00000404276.6

TSL:1MANE Select

HGVSc / HGVSpc.1100delCp.Thr367MetfsTer15

Exon rankExon 11 of 15

frameshift

Prot: ENSP00000385747.1UniProt: O96017-1

CHEK2 ENST00000382580.6

TSL:1

HGVSc / HGVSpc.1229delCp.Thr410MetfsTer15

Exon rankExon 12 of 16

frameshift

Prot: ENSP00000372023.2UniProt: O96017-9

CHEK2 ENST00000402731.6

TSL:1

HGVSc / HGVSpc.899delCp.Thr300MetfsTer15

Exon rankExon 9 of 13

frameshift

Prot: ENSP00000384835.2UniProt: A0A7P0MUT5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00172	AC:262	Hom:0	AN:152206	Cov:32
GnomAD2 exomes	AF: 0.00204	AC:509	Hom:	AN:248982	Cov:
GnomAD4 exome Warning	AF: 0.00220	AC:3205	Hom:5	AN:1459022	Cov:30
GnomAD4 genome	AF: 0.00172	AC:262	Hom:0	AN:152324	Cov:32
TOPMed (Bravo)	AF: 0.00100	AC:266	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000631	AC:62	Hom:1	AN:98332	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
Denmark Genome	AF: 0.0133	AC:4	Hom:	AN:300	Cov:
Turkish Variome	AF: 0.000206	AC:1	Hom:0	AN:4462	Cov:
UK10K	AF: 0.000793	AC:6	Hom:	AN:7562	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00320	91	28420	0.00284	82	28844
Epi25(Epilepsy)	0.00172	72	41958	0.00173	116	66888
SCHEMA(Schizophrenia)	0.000845	49	57998	0.000849	68	80062

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
21	-	-	not provided (22)
14	-	-	CHEK2-related cancer predisposition (15)
14	-	-	Familial cancer of breast (14)
13	-	-	Hereditary cancer-predisposing syndrome (13)
3	-	-	Colorectal cancer (3)
3	-	-	Inherited breast cancer and ovarian cancer (3)
3	-	-	Inherited prostate cancer (3)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
-	1	-	Astrocytoma (1)
1	-	-	Bone osteosarcoma (1)
1	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Breast and colorectal cancer, susceptibility to (1)
1	-	-	Breast cancer, susceptibility to (1)
1	-	-	Breast carcinoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Pathogenic	8.7

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs555607708;

hg19: chr22-29091856;

COSMIC: COSV60419771;

COSMIC: COSV60419771;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar