chr22-28696957-C-T

Variant names:

• chr22-28696957-C-T
• rs28909980
• NM_007194.4:c.1039G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PS3 PM1 PP3_Moderate PP5 BS2_Supporting

The NM_007194.4(CHEK2):​c.1039G>A​(p.Asp347Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000274 in 1,461,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000210981: Published functional studies demonstrate a damaging effect: loss of kinase activity, diminished growth rate after DNA damage (Ghosh 2006, Delimitsou 2019, Boonen 2021)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D347G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:2
• Conservation: PhyloP100: 6.20
• Publications: 18 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000210981: Published functional studies demonstrate a damaging effect: loss of kinase activity, diminished growth rate after DNA damage (Ghosh 2006, Delimitsou 2019, Boonen 2021); SCV004933782: Functional studies indicate this variant impacts protein function [PMID: 19782031, 16794575, 37449874, 34903604].; SCV000277636: "In multiple assays testing CHEK2 function, this variant showed functionally abnormal results (Ghosh JC et al. Cancer Res., 2006 Dec;66:11576-9; Delimitsou A et al. Hum. Mutat., 2019 Mar; Boonen RACM et al. Cancer Res, 2022 02;82:615-631; Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050)."; SCV000913583: Functional studies have shown this variant to be damaging to CHEK2 function in a DNA damage repair assay in yeast (PMID: 30851065) and that this variant impacts CHEK2 function in autophosphorylation and phosphorylation of KAP1 in mammalian cells (PMID: 34903604, 37449874).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 69 uncertain in NM_007194.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 22-28696957-C-T is Pathogenic according to our data. Variant chr22-28696957-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 182432.
• BS2: High AC in GnomAdExome4 at 40 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.1039G>A	p.Asp347Asn	missense	Exon 10 of 15	NP_009125.1	O96017-1
	CHEK2	NM_001005735.3		c.1168G>A	p.Asp390Asn	missense	Exon 11 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1132G>A	p.Asp378Asn	missense	Exon 11 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.1039G>A	p.Asp347Asn	missense	Exon 10 of 15	ENSP00000385747.1	O96017-1
	CHEK2	ENST00000382580.6	TSL:1	c.1168G>A	p.Asp390Asn	missense	Exon 11 of 16	ENSP00000372023.2	O96017-9
	CHEK2	ENST00000402731.6	TSL:1	c.838G>A	p.Asp280Asn	missense	Exon 8 of 13	ENSP00000384835.2	A0A7P0MUT5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251260 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: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461106 Hom.: 0 Cov.: 29 AF XY: 0.0000248 AC XY: 18 AN XY: 726892

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111386

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000183 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	-	Familial cancer of breast (5)
4	-	-	not provided (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.36		Loss of catalytic residue at N352 (P = 0.1251)
MVP		0.99
MPC		0.16
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.88
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs28909980; hg19: chr22-29092945;