rs767253467

Variant names:

• chr22-28719449-G-A
• rs767253467
• NM_007194.4:c.629C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28719449-G-A
• chr22-28719449-G-C
• chr22-28719449-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_007194.4(CHEK2):​c.629C>T​(p.Ser210Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000111 in 1,445,364 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S210S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.62
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 16 AD 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.629C>T	p.Ser210Leu	missense	Exon 5 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.758C>T	p.Ser253Leu	missense	Exon 6 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.722C>T	p.Ser241Leu	missense	Exon 6 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.629C>T	p.Ser210Leu	missense	Exon 5 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.758C>T	p.Ser253Leu	missense	Exon 6 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000403642.5	TSL:1	c.356C>T	p.Ser119Leu	missense	Exon 2 of 12	ENSP00000384919.1	O96017-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 232008 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1445364 Hom.: 0 Cov.: 28 AF XY: 0.00000696 AC XY: 5 AN XY: 718338

African (AFR) AF: 0.0000301 AC: 1 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25438

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84070

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1102680

Other (OTH) AF: 0.00 AC: 0 AN: 59682

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.0000250 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	1	-	Familial cancer of breast (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.33	T
Polyphen		0.0060	B
Vest4		0.28
MutPred		0.46		Gain of stability (P = 0.0644)
MVP		0.73
MPC		0.021
ClinPred		0.68	D
GERP RS		5.4
Varity_R		0.21
gMVP		0.40
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767253467; hg19: chr22-29115437;