22-28711961-G-T

Position:

chr22-28711961-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_007194.4(CHEK2):c.740C>A(p.Ala247Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,690 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: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.10

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.740C>A	p.Ala247Asp	missense_variant	6/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.740C>A	p.Ala247Asp	missense_variant	6/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251372

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135876

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727142

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2023	This missense variant replaces alanine with aspartic acid at codon 247 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant was detected in the compound heterozygous state with a known pathogenic variant in a sporadic colon carcinoma cell line and has been shown to reduce protein expression, stability, and kinase activity (PMID: 11719428, 34903604). In an international breast cancer case-control meta-analysis, this variant was detected in 1/60466 cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/251372 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 24, 2023	The p.A247D variant (also known as c.740C>A), located in coding exon 5 of the CHEK2 gene, results from a C to A substitution at nucleotide position 740. The alanine at codon 247 is replaced by aspartic acid, an amino acid with dissimilar properties. At this time, this variant has not been reported in individuals with CHEK2-related cancers; however, in vitro analysis in a colorectal cancer cell line has shown this variant results in an unstable CHEK2 protein (Lee SB et al. Cancer Res., 2001 Nov;61:8062-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2023

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies suggest a damaging effect: protein instability and reduced kinase activity (PMID: 11719428, 34903604); This variant is associated with the following publications: (PMID: 21765476, 23856246, 15162061, 24755471, 17721994, 22189968, 12393693, 18297428, 22385513, 27716909, 11719428, 34903604, 22419737, 19782031) -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2023

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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 11719428, 21765476, 34903604). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 422759). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 247 of the CHEK2 protein (p.Ala247Asp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;.;D;.;D;.;D;.;.;.;.;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

.;D;.;D;.;D;D;D;.;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

4.0

H;H;H;.;H;.;H;.;H;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.8

D;D;D;.;D;D;.;D;D;D;.;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D;.;D;D;.;D;D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;D;D;.;D;D;D;.;.;D

Polyphen

1.0

D;D;D;.;D;D;D;D;D;.;.;.;.

Vest4

0.96

MutPred

0.88

Loss of methylation at K245 (P = 0.0476);Loss of methylation at K245 (P = 0.0476);Loss of methylation at K245 (P = 0.0476);.;Loss of methylation at K245 (P = 0.0476);.;Loss of methylation at K245 (P = 0.0476);.;Loss of methylation at K245 (P = 0.0476);.;.;.;.;

MVP

0.98

MPC

0.18

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

1.0

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over