NM_007194.4:c.860A>T

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: 4 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: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		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).
	PM2Absent/extremely low in population databases		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	Prot: NP_009125.1 UniProt:
	CHEK2 NM_001005735.3		c.989A>T p.Lys330Met	missense	Exon 9 of 16	Prot: NP_001005735.1 UniProt:
	CHEK2 NM_001438293.1		c.953A>T p.Lys318Met	missense	Exon 9 of 16	Prot: NP_001425222.1

CHEK2 NM_007194.4

MANE Select

HGVSc / HGVSpc.860A>Tp.Lys287Met

Exon rankExon 8 of 15

missense

Prot: NP_009125.1UniProt: O96017-1

CHEK2 NM_001005735.3

HGVSc / HGVSpc.989A>Tp.Lys330Met

Exon rankExon 9 of 16

missense

Prot: NP_001005735.1UniProt: O96017-9

CHEK2 NM_001438293.1

HGVSc / HGVSpc.953A>Tp.Lys318Met

Exon rankExon 9 of 16

missense

Prot: NP_001425222.1

Ensembl Transcripts

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

CHEK2 ENST00000404276.6

TSL:1MANE Select

HGVSc / HGVSpc.860A>Tp.Lys287Met

Exon rankExon 8 of 15

missense

Prot: ENSP00000385747.1UniProt: O96017-1

CHEK2 ENST00000382580.6

TSL:1

HGVSc / HGVSpc.989A>Tp.Lys330Met

Exon rankExon 9 of 16

missense

Prot: ENSP00000372023.2UniProt: O96017-9

CHEK2 ENST00000402731.6

TSL:1

HGVSc / HGVSpc.659A>Tp.Lys220Met

Exon rankExon 6 of 13

missense

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:225074	Cov:
GnomAD4 exome	AF: 0.0000142	AC:20	Hom:0	AN:1408664	Cov:25
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000152	1	65632	0.00	0	128444

Showing 1 cohortAllele 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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
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
FuncVEP CTI	Benign	0.41
GPN-Star LLR	N/A	-7.7
GPN-Star score	N/A	7.7
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.30	T
Mutation Taster	N/A	30/70	disease causing
MutationAssessor	Benign	1.9	L
PhyloP100	Uncertain	5.9
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.012	D
Varity_R	N/A	0.73
VESM-3B	Benign	-10

Showing 30 of 30 scores

Splicing Scores

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

Showing 3 of 3 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.

1 no calibration

1 assay found for this variant.

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

CHEK2 Yeast Complementation in MMS

CHEK2 Yeast Complementation

• Gene: CHEK2
• Assay type: Cell fitness
• Mechanism: DNA damage checkpoint signaling
• Model system: Yeast (Saccharomyces cerevisiae)
• Score: 0.805 · p.Lys287Met (assay numbering)

Classified as

indeterminateUnclassified

This score is at approximately the 51th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs876659184;

hg19: chr22-29099541;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar