NM_007194.4:c.3G>C

Variant names:

• chr22-28734719-C-G
• rs786203977
• NM_007194.4:c.3G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_007194.4(CHEK2):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000137 in 1,461,312 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHEK2 NM_007194.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 46 codons. Genomic position: 28734586. Lost 0.083 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.3G>C	p.Met1?	start_lost	Exon 2 of 15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.3G>C	p.Met1?	start_lost	Exon 2 of 15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461312 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726914

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 07, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the translation initiator codon of CHEK2 mRNA. Because a downstream methionine at codon 46 may be used to initiate CHEK2 translation, the impact to this variant on translation is not known. To our knowledge, experimental functional studies of CHEK2 translation have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;T;T;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
PROVEAN	Benign	-0.65	N;N;N;N;N;.;N;N;N;N;N;.;N
REVEL	Uncertain	0.32
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		0.17	B;B;B;B;P;B;B;B;.;.;.;.;.
Vest4		0.78
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);Gain of catalytic residue at M1 (P = 0.0208);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203977; hg19: chr22-29130707;