rs876659184

Variant names:

• chr22-28703553-T-A
• rs876659184
• NM_007194.4:c.860A>T
• CHEK2 p.Lys287Met

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM1PM2

The NM_007194.4(CHEK2):c.860A>T (p.Lys287Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000142 (AC=20) in the gnomAD database across 1,408,664 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000122. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K287= (synonymous): Likely_benign (ClinVar VariationId 1764065, 1 star); p.K287N: Uncertain_significance (ClinVar VariationId 2505551, 1 star)

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.85
• 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, 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

Our verdict: Uncertain_significance. The variant received 4 points.

• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0).
• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000122 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00276) — PM2 moderate.

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.860A>T	p.Lys287Met	missense	Exon 8 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.989A>T	p.Lys330Met	missense	Exon 9 of 16	NP_001005735.1	O96017-9
	CHEK2	NM_001438293.1		c.953A>T	p.Lys318Met	missense	Exon 9 of 16	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.860A>T	p.Lys287Met	missense	Exon 8 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.989A>T	p.Lys330Met	missense	Exon 9 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.659A>T	p.Lys220Met	missense	Exon 6 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 225074 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000142 AC: 20 AN: 1408664 Hom.: 0 Cov.: 25 AF XY: 0.0000128 AC XY: 9 AN XY: 701356

African (AFR) AF: 0.00 AC: 0 AN: 32532

American (AMR) AF: 0.00 AC: 0 AN: 41850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25458

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.00 AC: 0 AN: 83194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000187 AC: 20 AN: 1069608

Other (OTH) AF: 0.00 AC: 0 AN: 58602

GnomAD4 genome Cov.: 31

Case/control cohorts

Cohort

Cases

Controls

SCHEMA (Schizophrenia)

1 / 65632AF: 0.0000152365

0 / 128444AF: 0

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

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	Familial cancer of breast (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.012	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
popEVE	Benign	-3.4
VESM-3B	Benign	-10
FuncVEP CTI	Benign	0.41
AlphaGenome AVI	Pathogenic	25
GPN-Star LLR		-7.7
GPN-Star score		7.7
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 13
Pangolin (max)	Benign	0.090

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.

Other links and lift over

dbSNP: rs876659184;

hg19: chr22-29099541;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar