22-28734721-T-C

Position:

• chr22-28734721-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_007194.4(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 0.00000137 in 1,461,310 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).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHEK2 NM_007194.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 2.92

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.1A>G	p.Met1?	start_lost	2/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.1A>G	p.Met1?	start_lost	2/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461310 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	This sequence change affects the initiator methionine of the CHEK2 mRNA. The next in-frame methionine is located at codon 46. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 216643). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 10, 2024	This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. Although the next in-frame methionine is located at codon 46, if initiation occurred at this position more than half of the SQ/TQ domain would be deleted and the SQ/TQ domain is critical for proper protein function. In addition, this, and other initiation codon variants, have been shown to be associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in the CHEK2 gene [PMID: 25085752]. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 20, 2024	The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the CHEK2 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 45 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 23, 2022	This variant results in the loss of the translation initiator methionine at codon 1 of the CHEK2 protein. The next in-frame methionine occurs at codon 46 and may serve as an alternative translation start site. Loss of these 45 N-terminal amino acids may impact the SQ/TQ motif (a.a. 19-69), but the significance of this is not well established. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. CHEK2 initiation codon variants are classified as uncertain significance in ClinVar (Variation ID: 187757, 216643, 460831, 920652, 947894, 1023013). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;T;T;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.037
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
PROVEAN	Benign	-0.65	N;N;N;N;N;.;N;N;N;N;N;.;N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;.;.
Polyphen		0.076	B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.79
MutPred		0.99		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.82
gMVP		0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224748; hg19: chr22-29130709;