rs17886163

Variant names:

• chr22-28695159-A-C
• rs17886163
• NM_007194.4:c.1343T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-28695159-A-C
• chr22-28695159-A-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.1343T>G​(p.Ile448Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,612,248 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I448V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (6 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 7.38
• Publications: 29 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
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

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

  Inheritance: AD 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 (MetaRNN=0.008066297).
• BP6: Variant 22-28695159-A-C is Benign according to our data. Variant chr22-28695159-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0051 (776/152298) while in subpopulation AFR AF = 0.0178 (741/41560). AF 95% confidence interval is 0.0168. There are 5 homozygotes in GnomAd4. There are 347 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 776 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.1343T>G	p.Ile448Ser	missense	Exon 12 of 15	NP_009125.1
	CHEK2	NM_001005735.3		c.1472T>G	p.Ile491Ser	missense	Exon 13 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1436T>G	p.Ile479Ser	missense	Exon 13 of 16	NP_001425222.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.1343T>G	p.Ile448Ser	missense	Exon 12 of 15	ENSP00000385747.1
	CHEK2	ENST00000382580.6	TSL:1	c.1472T>G	p.Ile491Ser	missense	Exon 13 of 16	ENSP00000372023.2
	CHEK2	ENST00000402731.6	TSL:1	c.1142T>G	p.Ile381Ser	missense	Exon 10 of 13	ENSP00000384835.2

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 776 AN: 152180 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00140 AC: 351 AN: 251084 AF XY: 0.000988

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000530 AC: 774 AN: 1459950 Hom.: 6 Cov.: 30 AF XY: 0.000439 AC XY: 319 AN XY: 726396

African (AFR) AF: 0.0203 AC: 677 AN: 33402

American (AMR) AF: 0.000447 AC: 20 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1110386

Other (OTH) AF: 0.000845 AC: 51 AN: 60322

GnomAD4 genome AF: 0.00510 AC: 776 AN: 152298 Hom.: 5 Cov.: 32 AF XY: 0.00466 AC XY: 347 AN XY: 74472

African (AFR) AF: 0.0178 AC: 741 AN: 41560

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00571

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00187 AC: 227

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial cancer of breast (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	4	not specified (5)
-	-	2	CHEK2-related cancer predisposition (2)
-	-	1	Breast and/or ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.077	T
Eigen	Benign	0.028
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PhyloP100		7.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.14
Sift	Benign	0.71	T
Sift4G	Benign	0.75	T
Polyphen		0.12	B
Vest4		0.57
MVP		0.68
MPC		0.045
ClinPred		0.040	T
GERP RS		5.9
Varity_R		0.49
gMVP		0.82
Mutation Taster		=39/61	disease causing

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: rs17886163; hg19: chr22-29091147; COSMIC: COSV99049072; COSMIC: COSV99049072;