rs200050883

Variant names:

• chr22-28695190-C-A
• rs200050883
• NM_007194.4:c.1312G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28695190-C-A
• chr22-28695190-C-G
• chr22-28695190-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_007194.4(CHEK2):​c.1312G>T​(p.Asp438Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000376 in 1,613,498 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D438V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21 B:13 O:2
• Conservation: PhyloP100: 4.62
• Publications: 51 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045587093).
• BP6: Variant 22-28695190-C-A is Benign according to our data. Variant chr22-28695190-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128056.
• BS2: High AC in GnomAd4 at 57 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.1312G>T	p.Asp438Tyr	missense	Exon 12 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.1441G>T	p.Asp481Tyr	missense	Exon 13 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1405G>T	p.Asp469Tyr	missense	Exon 13 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.1312G>T	p.Asp438Tyr	missense	Exon 12 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.1441G>T	p.Asp481Tyr	missense	Exon 13 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.1111G>T	p.Asp371Tyr	missense	Exon 10 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000386 AC: 97 AN: 251038 AF XY: 0.000339

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000376 AC: 549 AN: 1461236 Hom.: 2 Cov.: 30 AF XY: 0.000359 AC XY: 261 AN XY: 726952

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.000112 AC: 5 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86236

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53402

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5760

European-Non Finnish (NFE) AF: 0.000362 AC: 402 AN: 1111494

Other (OTH) AF: 0.000265 AC: 16 AN: 60362

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74442

African (AFR) AF: 0.0000963 AC: 4 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000381 Hom.: 1

Bravo AF: 0.000280

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.00109

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	7	4	not provided (12)
-	3	3	Familial cancer of breast (6)
-	3	2	Hereditary cancer-predisposing syndrome (5)
-	2	1	not specified (3)
-	2	-	CHEK2-related cancer predisposition (3)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Carcinoma of colon (1)
-	-	1	CHEK2-related disorder (1)
-	1	-	Familial cancer of breast;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.83
MPC		0.15
ClinPred		0.16	T
GERP RS		5.8
Varity_R		0.82
gMVP		0.74
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200050883; hg19: chr22-29091178; COSMIC: COSV105248010;