22-28719414-T-C

Variant names:

• chr22-28719414-T-C
• rs786203472
• NM_007194.4:c.664A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 10P and 2B. PVS1 PS1_Moderate BP6 BS2_Supporting

The NM_001257387.3(CHEK2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000766 in 1,436,730 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: CHEK2 NM_001257387.3 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.35
• 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_pathogenic. The variant received 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 150 pathogenic variants. Next in-frame start position is after 83 codons. Genomic position: 28699936. Lost 0.255 part of the original CDS.
• PS1: Another start lost variant in NM_001257387.3 (CHEK2) was described as [Likely_pathogenic] in ClinVar
• BP6: Variant 22-28719414-T-C is Benign according to our data. Variant chr22-28719414-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 187101.
• BS2: High AC in GnomAdExome4 at 11 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_001257387.3. 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.664A>G	p.Met222Val	missense	Exon 5 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001257387.3		c.1A>G	p.Met1?	start_lost	Exon 6 of 16	NP_001244316.1
	CHEK2	NM_001437942.1		c.1A>G	p.Met1?	start_lost	Exon 4 of 14	NP_001424871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.664A>G	p.Met222Val	missense	Exon 5 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.793A>G	p.Met265Val	missense	Exon 6 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000403642.5	TSL:1	c.391A>G	p.Met131Val	missense	Exon 2 of 12	ENSP00000384919.1	O96017-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000766 AC: 11 AN: 1436730 Hom.: 0 Cov.: 27 AF XY: 0.00000700 AC XY: 5 AN XY: 713882

African (AFR) AF: 0.00 AC: 0 AN: 32982

American (AMR) AF: 0.00 AC: 0 AN: 42102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.00 AC: 0 AN: 39386

South Asian (SAS) AF: 0.00 AC: 0 AN: 82874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5090

European-Non Finnish (NFE) AF: 0.00000911 AC: 10 AN: 1097408

Other (OTH) AF: 0.0000169 AC: 1 AN: 59332

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.92	N
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.087
Sift	Benign	0.39	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.47		Loss of ubiquitination at K224 (P = 0.1072)
MVP		0.42
MPC		0.021
ClinPred		0.39	T
GERP RS		3.1
Varity_R		0.22
gMVP		0.36
Mutation Taster		=9/191	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs786203472; hg19: chr22-29115402; COSMIC: COSV105247875;