chr22-28695868-AG-A

Variant names:

• chr22-28695868-AG-A
• rs555607708
• NM_007194.4:c.1100delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PVS1 PP5 BS2_Supporting

The NM_001005735.3(CHEK2):​c.1229delC​(p.Thr410MetfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 152,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T410T) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHEK2 NM_001005735.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:86 U:1 O:2
• Conservation: PhyloP100: 8.67
• Publications: 847 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
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD 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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 22-28695868-AG-A is Pathogenic according to our data. Variant chr22-28695868-AG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128042.
• BS2: High AC in GnomAd4 at 262 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_001005735.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.1100delC	p.Thr367MetfsTer15	frameshift	Exon 11 of 15	NP_009125.1
	CHEK2	NM_001005735.3		c.1229delC	p.Thr410MetfsTer15	frameshift	Exon 12 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1193delC	p.Thr398MetfsTer15	frameshift	Exon 12 of 16	NP_001425222.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.1100delC	p.Thr367MetfsTer15	frameshift	Exon 11 of 15	ENSP00000385747.1
	CHEK2	ENST00000382580.6	TSL:1	c.1229delC	p.Thr410MetfsTer15	frameshift	Exon 12 of 16	ENSP00000372023.2
	CHEK2	ENST00000402731.6	TSL:1	c.899delC	p.Thr300MetfsTer15	frameshift	Exon 9 of 13	ENSP00000384835.2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00204 AC: 509 AN: 248982 AF XY: 0.00203

Gnomad AFR exome AF: 0.000395

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00220 AC: 3205 AN: 1459022 Hom.: 5 Cov.: 30 AF XY: 0.00213 AC XY: 1548 AN XY: 726030

African (AFR) AF: 0.000150 AC: 5 AN: 33422

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86200

European-Finnish (FIN) AF: 0.00848 AC: 453 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00236 AC: 2620 AN: 1109400

Other (OTH) AF: 0.00148 AC: 89 AN: 60306

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74480

African (AFR) AF: 0.000265 AC: 11 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00904 AC: 96 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68030

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

Alfa AF: 0.000595 Hom.: 1

Bravo AF: 0.00100

EpiCase AF: 0.00185

EpiControl AF: 0.00130

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
21	-	-	not provided (22)
14	-	-	Familial cancer of breast (14)
12	-	-	Hereditary cancer-predisposing syndrome (12)
9	-	-	CHEK2-related cancer predisposition (10)
3	-	-	Colorectal cancer (3)
3	-	-	Inherited breast cancer and ovarian cancer (3)
2	-	-	Breast and/or ovarian cancer (2)
-	1	-	Astrocytoma (1)
1	-	-	Bone osteosarcoma (1)
1	-	-	Bone osteosarcoma;C2931456:Familial prostate cancer;C5882668:CHEK2-related cancer predisposition (1)
1	-	-	Breast and colorectal cancer, susceptibility to (1)
1	-	-	Breast cancer, susceptibility to (1)
1	-	-	Breast carcinoma (1)
1	-	-	Breast neoplasm (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs555607708; hg19: chr22-29091856; COSMIC: COSV60419771; COSMIC: COSV60419771;