NM_007194.4:c.190G>A

Variant names:

• chr22-28734532-C-T
• rs141568342
• NM_007194.4:c.190G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PS3 PP5 BP4 BS2_Supporting

The NM_007194.4(CHEK2):​c.190G>A​(p.Glu64Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,613,790 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000902646: Multiple functional studies have shown this variant to disrupt CHEK2 function in kinase assays and DNA damage response (PMID:16835864, 22419737, 31050813, 33606978, 34903604).; SCV000254934: Experimental studies have shown that this missense change affects CHEK2 function (PMID:16835864, 22419737).; SCV000266168: "This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737)."; SCV000149918: Published functional studies demonstrate intermediate to impaired auto-phosphorylation and kinase activity, with some conflicting results (PMID:16835864, 22419737, 30851065, 31050813, 34903604, 37449874); SCV006325073: Functional cell based assay showed reduction in phosphorylation and kinase activity (PMID:16835864, 31050813); SCV000917231: Other laboratories have reported a reduction in CHEK2-specific phosphorylation and kinase activities in vitro (examples- Wu_2006, Kleiblova_2019).; SCV003843063: Functional assays have reported that this variant results in reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID:16835864, 31050813); SCV000806876: Functional studies suggest this variant may negatively affect cellular response to DNA damage (Roeb. 2012. PubMed ID: 22419737) and partially reduce CHEK2 kinase activity (Wu et al. 2006. PubMed ID: 16835864).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E64V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:23 O:3
• Conservation: PhyloP100: 3.49
• Publications: 43 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000902646: Multiple functional studies have shown this variant to disrupt CHEK2 function in kinase assays and DNA damage response (PMID: 16835864, 22419737, 31050813, 33606978, 34903604).; SCV000254934: Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737).; SCV000266168: "This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737)."; SCV000149918: Published functional studies demonstrate intermediate to impaired auto-phosphorylation and kinase activity, with some conflicting results (PMID: 16835864, 22419737, 30851065, 31050813, 34903604, 37449874); SCV006325073: Functional cell based assay showed reduction in phosphorylation and kinase activity (PMID: 16835864, 31050813); SCV000917231: Other laboratories have reported a reduction in CHEK2-specific phosphorylation and kinase activities in vitro (examples- Wu_2006, Kleiblova_2019).; SCV003843063: Functional assays have reported that this variant results in reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID: 16835864, 31050813); SCV000806876: Functional studies suggest this variant may negatively affect cellular response to DNA damage (Roeb. 2012. PubMed ID: 22419737) and partially reduce CHEK2 kinase activity (Wu et al. 2006. PubMed ID: 16835864).
• PP5: Variant 22-28734532-C-T is Pathogenic according to our data. Variant chr22-28734532-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128068.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13926247). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 22 AD,Unknown gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.190G>A	p.Glu64Lys	missense	Exon 2 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.190G>A	p.Glu64Lys	missense	Exon 2 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.190G>A	p.Glu64Lys	missense	Exon 2 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.190G>A	p.Glu64Lys	missense	Exon 2 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.190G>A	p.Glu64Lys	missense	Exon 2 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.190G>A	p.Glu64Lys	missense	Exon 1 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151916 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251468 AF XY: 0.000140

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.000153 AC XY: 111 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000213 AC: 237 AN: 1111994

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151916 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74182

African (AFR) AF: 0.0000726 AC: 3 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	7	-	not provided (10)
4	4	-	Familial cancer of breast (9)
4	4	-	Hereditary cancer-predisposing syndrome (8)
2	3	-	CHEK2-related cancer predisposition (5)
1	2	-	Hereditary breast ovarian cancer syndrome (3)
1	1	-	Breast and/or ovarian cancer (2)
1	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Breast and colorectal cancer, susceptibility to (1)
1	-	-	CHEK2-related disorder (1)
-	1	-	Malignant tumor of breast (1)
-	1	-	not specified (1)
1	-	-	Predisposition to cancer (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.057	T
Sift4G	Benign	0.14	T
Polyphen		0.18	B
Vest4		0.21
MVP		0.97
MPC		0.021
ClinPred		0.049	T
GERP RS		4.4
PromoterAI		0.0072	Neutral
Varity_R		0.14
gMVP		0.22
Mutation Taster		=0/100	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: rs141568342; hg19: chr22-29130520; COSMIC: COSV105899911;