rs200451612

Positions:

chr22-28719415-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001257387.2(CHEK2):c.-1C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,589,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

CHEK2
NM_001257387.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4O:1

Conservation

PhyloP100: 1.80

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07397741).

BP6

Variant 22-28719415-G-C is Benign according to our data. Variant chr22-28719415-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142342.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.663C>G	p.Ile221Met	missense_variant	5/15	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.663C>G	p.Ile221Met	missense_variant	5/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

228874

Hom.:

AF XY:

0.0000324

AC XY:

AN XY:

123594

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.0000944

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000188

AC:

AN:

1437434

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

714216

show subpopulations

Gnomad4 AFR exome

AF:

0.000606

Gnomad4 AMR exome

AF:

0.0000948

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:

0.00

Gnomad4 OTH exome

AF:

0.0000506

GnomAD4 genome

AF:

0.000263

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000771

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.000457

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000416

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 09, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 221 of the CHEK2 protein (p.Ile221Met). This variant is present in population databases (rs200451612, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 21244692). ClinVar contains an entry for this variant (Variation ID: 142342). 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. 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	Counsyl	Jun 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2022	This missense variant replaces isoleucine with methionine at codon 221 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant to have neutral effect on CHEK2 protein function in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 32936981). This variant has also been identified in 16/260244 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in seven females over age 70 who lack personal history of cancer (FLOSSIES, https://whi.color.com/variant/22-29115403-G-C). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 23, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27720647, 19782031, 21244692, 26787654, 27153395, 32936981, 22419737, 37449874, 30851065, 32832836) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 18, 2024	The CHEK2 c.663C>G (p.Ile221Met) variant has been reported in the published literature in individuals with a personal and/or family history of breast/ovarian cancer (PMIDs: 21244692 (2011), 27153395 (2016), 32936981 (2021)). Functional studies reported this variant to have no damaging effect on CHEK2 function (PMIDs: 30851065 (2019), 37449874 (2023)). The frequency of this variant in the general population, 0.00052 (12/22912 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The CHEK2 c.-1C>G variant is located in the 5' untranslated region. This variant has been identified in 4 individuals with breast and/or ovarian cancer (Supplementary Table 1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Table S4, Maxwell et al. 2016. PubMed ID: 27153395). Functional assessment using a combination of silico tools produced conflicting results, however assessment using a yeast functional assay suggested this variant is benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant has been observed with a subpopulation frequency of 0.05% in the gnomAD database, which may be too common to be a primary cause of disease. This variant is classified in ClinVar as uncertain significance (7) and likely benign (4) (https://www.ncbi.nlm.nih.gov/clinvar/variation/142342/). Although, we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 09, 2024

Variant summary: CHEK2 c.663C>G (p.Ile221Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 231092 control chromosomes (gnomAD, Le Calves-Kelm_2011), predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database, which is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). Additionally, the variant was reported in 6/2559 African American women (carrier frequency of 0.002345), who were older than 70 years of age with no personal history of cancer (FLOSSIES database). These data suggest that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.663C>G has been reported in the literature in one individual affected with Breast Cancer, without evidence for causality (e.g. Le Calvez-Kelm 2011). Experimental evidence from a yeast complementation assay (Delimitsou_2019), CHEK2-complementation assay, and KAP1 phosphorylation assays (Stolarova_2023) indicated that the variant did not have a damaging effect on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 21244692, 27720647, 37449874, 26787654). ClinVar contains an entry for this variant (Variation ID: 142342). Based on the evidence outlined above, the variant was classified as likely benign. -

Predisposition to cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Sep 14, 2023

The CHEK2 c.663C>G (p.Ile221Met) missense change has a maximum subpopulation frequency of 0.052% in gnomAD v2.1.1 and a maximum subpopulation frequency of 0.096% in gnomAD v3.2.1. The in silico tool REVEL predicts a benign effect on protein function and functional studies are in agreement with this prediction. A yeast-based growth assay indicated that this variant behaved similar to the wild-type (PMID: 30851065) and CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells also indicated that this variant behaved similar to wild-type (PMID: 37449874). Although this variant has been reported in an individual diagnosed with breast cancer prior to age 45 (PMID: 21244692), seven individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com). In summary, this variant meets criteria to be classified as likely benign. -

CHEK2-related cancer predisposition

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 11-01-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.074

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

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.2

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

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.84

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

REVEL

Benign

0.20

Sift

Benign

0.11

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

Sift4G

Benign

0.18

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

Polyphen

0.95

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

Vest4

0.60

MVP

0.54

MPC

0.15

ClinPred

0.097

GERP RS

5.5

Varity_R

0.61

gMVP

0.41

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