22-28725091-T-C

Position:

chr22-28725091-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate

The NM_007194.4(CHEK2):c.478A>G(p.Ile160Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I160K?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.37

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:

CHEK2 (HGNC:):

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a strand (size 8) in uniprot entity CHK2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_007194.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-28725089-TA-TTT is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.24889055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.478A>G	p.Ile160Val	missense_variant	4/15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.478A>G	p.Ile160Val	missense_variant	4/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135892

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:

0.00000889

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727212

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:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

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	Ambry Genetics	May 18, 2023	The p.I160V variant (also known as c.478A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 478. The isoleucine at codon 160 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in an individual diagnosed with breast cancer (Megid TBC et al. Front Oncol, 2022 Aug;12:873395). This alteration has also been identified in an individual diagnosed with renal cell cancer (Yngvadottir B et al. Hum Mol Genet, 2022 Aug;31:3001-3011). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 18, 2023	This missense variant replaces isoleucine with valine at codon 160 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000071, 36003761; Color internal data) and in an individual affected with familial breast and thyroid cancer (PMID: 32443704). One of the individuals affected with breast cancer also carried a pathogenic variant in the BRCA2 gene that could explain the observed phenotype (PMID: 36003761). This variant has been identified in 3/282814 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. -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 160 of the CHEK2 protein (p.Ile160Val). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 36003761). ClinVar contains an entry for this variant (Variation ID: 232725). 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 tolerated. 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. -

Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 27, 2021

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 16, 2017

Variant summary: The CHEK2 c.478A>G (p.Ile160Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent from 121352 control chromosomes. In addition, a clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.068

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.026

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.6

L;L;L;L;.;L;L;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.75

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

REVEL

Uncertain

0.41

Sift

Benign

0.13

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

Sift4G

Benign

0.24

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

Polyphen

0.34

B;B;B;B;B;B;B;.;.;.;.

Vest4

0.49

MutPred

0.56

Gain of phosphorylation at Y156 (P = 0.0894);Gain of phosphorylation at Y156 (P = 0.0894);Gain of phosphorylation at Y156 (P = 0.0894);Gain of phosphorylation at Y156 (P = 0.0894);.;Gain of phosphorylation at Y156 (P = 0.0894);Gain of phosphorylation at Y156 (P = 0.0894);.;Gain of phosphorylation at Y156 (P = 0.0894);Gain of phosphorylation at Y156 (P = 0.0894);Gain of phosphorylation at Y156 (P = 0.0894);

MVP

0.81

MPC

0.028

ClinPred

0.25

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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