22-28712009-C-T

Variant names:

Variant summary

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

The NM_007194.4(CHEK2):c.692G>A(p.Cys231Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,611,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.79

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.692G>A	p.Cys231Tyr	missense_variant	Exon 6 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.692G>A	p.Cys231Tyr	missense_variant	Exon 6 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460172

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726492

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150868

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73642

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Jan 02, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C231Y variant (also known as c.692G>A), located in coding exon 5 of the CHEK2 gene, results from a G to A substitution at nucleotide position 692. The cysteine at codon 231 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). 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. -

Familial cancer of breast

Uncertain:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 30303537). ClinVar contains an entry for this variant (Variation ID: 460851). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 231 of the CHEK2 protein (p.Cys231Tyr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;T;.;T;.;T;.;.;.;.;.;.

Eigen

Benign

-0.062

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.64

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

MetaSVM

Benign

-0.40

MutationAssessor

Benign

-1.6

N;N;N;.;N;.;N;.;N;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.8

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

REVEL

Uncertain

0.35

Sift

Uncertain

0.0090

D;D;D;.;D;T;.;T;D;T;.;D;T

Sift4G

Benign

0.26

T;T;T;.;T;T;.;T;T;T;.;.;D

Polyphen

0.72

P;D;P;.;P;P;P;D;D;.;.;.;.

Vest4

0.91

MutPred

0.71

Gain of phosphorylation at C231 (P = 0.0558);Gain of phosphorylation at C231 (P = 0.0558);Gain of phosphorylation at C231 (P = 0.0558);.;Gain of phosphorylation at C231 (P = 0.0558);.;Gain of phosphorylation at C231 (P = 0.0558);.;Gain of phosphorylation at C231 (P = 0.0558);.;.;.;.;

MVP

0.82

MPC

0.18

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.69

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