NM_007194.4:c.910A>G

Variant names:

• chr22-28699936-T-C
• rs769436449
• NM_007194.4:c.910A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_007194.4(CHEK2):​c.910A>G​(p.Met304Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000124 in 1,612,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M304K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense, splice_region
• Scores: Splicing: ADA: 0.1505
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 6.76
• Publications: 6 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32119733).
• BS2: High AC in GnomAd4 at 5 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.910A>G	p.Met304Val	missense splice_region	Exon 9 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.1039A>G	p.Met347Val	missense splice_region	Exon 10 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1003A>G	p.Met335Val	missense splice_region	Exon 10 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.910A>G	p.Met304Val	missense splice_region	Exon 9 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.1039A>G	p.Met347Val	missense splice_region	Exon 10 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.709A>G	p.Met237Val	missense splice_region	Exon 7 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151992 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250794 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460016 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 726228

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.000179 AC: 8 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110592

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151992 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.000262 AC: 4 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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: 10570

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Familial cancer of breast (3)
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	3	-	not provided (3)
-	1	-	CHEK2-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.43	N
PhyloP100		6.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Benign	0.38	T
Sift4G	Benign	0.30	T
Polyphen		0.78	P
Vest4		0.84
MVP		0.63
MPC		0.022
ClinPred		0.15	T
GERP RS		5.7
Varity_R		0.55
gMVP		0.54
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.010		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: rs769436449; hg19: chr22-29095924;