rs199749372

chr22-28719417-T-Cchr22-28719417-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007194.4(CHEK2):c.661A>G(p.Ile221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,591,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I221M) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 2.97

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11908299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.661A>G	p.Ile221Val	missense_variant	5/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.661A>G	p.Ile221Val	missense_variant	5/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152172

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000131

AC:

AN:

229264

Hom.:

AF XY:

0.00

AC XY:

AN XY:

123858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000315

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:

0.0000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1439110

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

715084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000236

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74484

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 26, 2018	The CHEK2 c.661A>G; p.Ile221Val variant (rs199749372), to our knowledge, is not reported in the medical literature but is reported by multiple laboratories in ClinVar (Variation ID: 140835). This variant is found in the general population with an overall allele frequency of 0.003% (1/30956 alleles) in the Genome Aggregation Database. The isoleucine at codon 221 is moderately conserved but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Ile221Val variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CHEK2: BP1, BP4, BS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2022	Published functional study demonstrates no damaging effect: normal cell growth after MMS-induced DNA damage (Delimitsou et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.790A>G, p.Ile264Val; This variant is associated with the following publications: (PMID: 27978560, 31398194, 31241222, 31106920, 30851065, 19782031, 22419737, 29769011) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2023	This missense variant replaces isoleucine with valine at codon 221 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). Functional studies have shown this variant to have a neutral effect on CHEK2 DNA damage repair activity in a yeast complementation assay (PMID: 30851065), and intermediate impact on KAP1 phosphorylation and neutral impact CHEK2 autophosphorylation in a mammalian cell complementation assay (PMID: 37449874). This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). In a large breast cancer case-control meta-analysis, this variant was reported in 4/73048 cases and 2/88658 unaffected controls (PMID: 37449874). This variant has been identified in 4/260646 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	Aug 30, 2023	The p.I221V variant (also known as c.661A>G), located in coding exon 4 of the CHEK2 gene, results from an A to G substitution at nucleotide position 661. The isoleucine at codon 221 is replaced by valine, an amino acid with highly similar properties. This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). In another functional study assessing CHEK2-complementation in human RPE1-CHEK2-knockout cells, this alteration was reported as functional through quantification of CHK2 autophosphorylation but intermediate in KAP1 phosphorylation (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This variant has been reported in cohorts of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569), African American males with prostate cancer (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43), and breast cancer cases and controls (Decker B et al. J Med Genet, 2017 11;54:732-741, Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Dorling L et al. N Engl J Med, 2021 Feb4;384(5):428-39). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 221 of the CHEK2 protein (p.Ile221Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 140835). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 27, 2023	- -

CHEK2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

The CHEK2 c.661A>G variant is predicted to result in the amino acid substitution p.Ile221Val. This variant has been reported in an individual with colorectal cancer and in a breast cancer cohort study (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560; Table S5, Decker et al. 2017. PubMed ID: 28779002). Experimental studies using a yeast-based assay suggest this variant is benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0031% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29115405-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/140835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.091

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

Eigen

Benign

-0.10

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.0063

MetaRNN

Benign

0.12

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.090

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.11

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

REVEL

Benign

0.13

Sift

Benign

0.28

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

Sift4G

Benign

0.50

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

Polyphen

0.015

B;P;B;B;B;B;P;P;.

Vest4

0.56

MVP

0.45

MPC

0.021

ClinPred

0.19

GERP RS

5.5

Varity_R

0.25

gMVP

0.31

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