rs145754558

Variant names:

• chr22-28719499-G-A
• rs145754558
• NM_007194.4:c.593-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28719499-G-A
• chr22-28719499-G-C
• chr22-28719499-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007194.4(CHEK2):​c.593-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,457,612 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (21 hom.)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.235
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-28719499-G-A is Benign according to our data. Variant chr22-28719499-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0014 (1825/1305342) while in subpopulation EAS AF = 0.0101 (386/38162). AF 95% confidence interval is 0.00928. There are 21 homozygotes in GnomAdExome4. There are 893 alleles in the male GnomAdExome4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 359 AD gene.

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.593-14C>T		intron	N/A	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.722-14C>T		intron	N/A	NP_001005735.1
	CHEK2	NM_001438293.1		c.686-14C>T		intron	N/A	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.593-14C>T		intron	N/A	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.722-14C>T		intron	N/A	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.482+5387C>T		intron	N/A	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00904

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00312 AC: 612 AN: 195858 AF XY: 0.00294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000347

Gnomad ASJ exome AF: 0.00257

Gnomad EAS exome AF: 0.00802

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.000620

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00140 AC: 1825 AN: 1305342 Hom.: 21 Cov.: 20 AF XY: 0.00137 AC XY: 893 AN XY: 653132

African (AFR) AF: 0.00 AC: 0 AN: 30338

American (AMR) AF: 0.0000502 AC: 2 AN: 39860

Ashkenazi Jewish (ASJ) AF: 0.00228 AC: 56 AN: 24594

East Asian (EAS) AF: 0.0101 AC: 386 AN: 38162

South Asian (SAS) AF: 0.000252 AC: 20 AN: 79412

European-Finnish (FIN) AF: 0.0194 AC: 989 AN: 50928

Middle Eastern (MID) AF: 0.000187 AC: 1 AN: 5358

European-Non Finnish (NFE) AF: 0.000294 AC: 289 AN: 981876

Other (OTH) AF: 0.00150 AC: 82 AN: 54814

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00906 AC: 47 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0202 AC: 214 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.00839 AC: 29 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Familial cancer of breast (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	CHEK2-related cancer predisposition (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

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: rs145754558; hg19: chr22-29115487;