22-28695752-C-T

Position:

chr22-28695752-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_007194.4(CHEK2):c.1217G>A(p.Arg406His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:7

Conservation

PhyloP100: 1.53

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025272042).

BP6

Variant 22-28695752-C-T is Benign according to our data. Variant chr22-28695752-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142760.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=5}. Variant chr22-28695752-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1217G>A	p.Arg406His	missense_variant	11/15	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.1217G>A	p.Arg406His	missense_variant	11/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000283

AC:

AN:

250750

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000206

AC:

301

AN:

1461410

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000118

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Aug 13, 2024	According to the ACMG SVI adaptation criteria we chose these criteria: BP4 (supporting benign): REVEL 0.14, BS1 (strong benign): laut Canvig - => ATM-VCEP: FAF > 0,5%; South asians: 0,16% in gnomAD V2 und V4, 0,1% in gnomAD V3 -
Uncertain significance, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Uncertain significance, criteria provided, single submitter	research	Cancer Genomics Group, Japanese Foundation For Cancer Research	May 01, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 16, 2018	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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	This variant is denoted CHEK2 c.1217G>A at the cDNA level, p.Arg406His (R406H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in several individuals with breast cancer (Novak 2008, Soumittra 2009, Caminsky 2016, Tung 2016) and in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015), but has also been observed in healthy controls (Novak 2008). In a yeast complementation assay, cells transformed with this variant demonstrated cell growth and survival comparable to wild type (Yilmaz 2014). Although this variant was observed in large population cohorts, data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Arg406His is located in the kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Arg406His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 30, 2024	The CHEK2 c.1217G>A (p.Arg406His) variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 18706089 (2008), 19656415 (2009), 25186627 (2015), 26898890 (2016), 26976419 (2016), 30303537 (2019), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)) and suspected of Lynch syndrome (PMID: 25980754 (2015)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), 31050813 (2019), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). In addition, functional studies suggest that the variant protein has normal DNA damage repair activity (PMID: 30851065 (2019), Yilmaz et al (2014, http://dx.doi.org/10.4236/abb.2014.54046) and intermediate to normal kinase activity (PMID: 31050813 (2019)). The frequency of this variant in the general population, 0.0016 (50/30616 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 02, 2024

Variant summary: CHEK2 c.1217G>A (p.Arg406His) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250750 control chromosomes, predominantly at a frequency of 0.0016 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), however this data must be interpreted with caution as the sequencing techology utalized does not distinguish between this gene and highly homologous pseudogenes. c.1217G>A has been reported in the literature in individuals affected with breast cancer (examples- Soumitra_2009, Tung_2016, Girard_2019) and in an individual with Lynch Syndrome (Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least two publications report experimental evidence evaluating an impact on CHEK2 function in yeast and find no damaging effects for the variant (Yilmaz_2014, Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 19656415, 25980754, 25186627, 26976419, 30851065, 30303537). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=5) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 17, 2023

- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CHEK2 p.Arg406His variant was identified in 12 of 9230 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer, lynch syndrome and was present in 22 of 13146 control chromosomes (frequency: 0.002) from healthy individuals (Caminsky 2016, Novak 2008, Soumittra 2009, Tung 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs200649225) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Invitae; as uncertain significance by GeneDx), Clinvitae, MutDB, and Zhejiang University databases. The variant was not identified in the Cosmic database. The variant was identified in control databases in 74 of 276652 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23964 chromosomes (freq: 0.00004), Latino in 3 of 34406 chromosomes (freq: 0.0001), European in 18 of 126232 chromosomes (freq: 0.0001), and South Asian in 52 of 30782 chromosomes (freq: 0.002); but not in the Other, Ashkenazi Jewish, East Asian, or Finnish populations. Yeast cells carrying the R406H variant grew at a rate similar to those carrying the wild type CHEK2, in In vitro complementation assay by Yilmaz (2014), and suggests the variant does not abrogate the function of CHEK2. The p.Arg406 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

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

Eigen

Benign

0.083

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.054

MetaRNN

Benign

0.025

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

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

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.15

Sift

Benign

0.062

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

Sift4G

Benign

0.086

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

Polyphen

1.0

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

Vest4

0.46

MVP

0.72

MPC

0.13

ClinPred

0.13

GERP RS

3.5

Varity_R

0.25

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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