22-28703507-T-G

Position:

chr22-28703507-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_007194.4(CHEK2):c.906A>C(p.Glu302Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000974 in 1,437,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 1 hom. )

Consequence

CHEK2
NM_007194.4 missense, splice_region

Scores

Splicing: ADA: 0.0006935

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 0.997

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 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.906A>C	p.Glu302Asp	missense_variant, splice_region_variant	8/15	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.906A>C	p.Glu302Asp	missense_variant, splice_region_variant	8/15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000296

AC:

AN:

202734

Hom.:

AF XY:

0.0000459

AC XY:

AN XY:

108872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000688

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:

0.0000466

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1285706

Hom.:

Cov.:

AF XY:

0.0000109

AC XY:

AN XY:

644066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000508

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:

0.00000830

Gnomad4 OTH exome

AF:

0.0000184

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 30, 2023	The p.E302D variant (also known as c.906A>C), located in coding exon 7 of the CHEK2 gene, results from an A to C substitution at nucleotide position 906. The glutamic acid at codon 302 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands diagnosed with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). This alteration behaved as semi-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). This alteration has also been reported in 2/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 28, 2023	This missense variant replaces glutamic acid with aspartic acid at codon 302 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). A functional study has demonstrated an intermediate impact of this variant on CHEK2 protein function in a yeast-based DNA damage response assay (PMID: 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 29522266, 30613976). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 3/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000406). This variant has been identified in 8/234112 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2024	Variant summary: CHEK2 c.906A>C (p.Glu302Asp) results in a 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3e-05 in 202734 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.906A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Tsaousis_2019, Rizzolo_2019, Bucalo_2023) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37262986, 30613976, 31159747). ClinVar contains an entry for this variant (Variation ID: 128087). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 05, 2024	The CHEK2 c.906A>C (p.Glu302Asp) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 30613976 (2019), 29522266 (2018)) and colorectal cancer (PMID: 33298767 (2021)). A yeast-based functional study indicates this variant has an intermediate impact on CHEK2 DNA repair activity (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.000059 (6/101258 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2022	Published functional studies are inconclusive: intermediate response to DNA damage (Delimitsou 2019); Identified in individuals with personal or family history of breast/ovarian cancer (Rizzolo 2019, Tsaousis 2019, Vargas-Parra 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.1035A>C; p.Glu345Asp; This variant is associated with the following publications: (PMID: 31159747, 22419737, 19782031, 32906215, 30613976, 33320972, 30851065) -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 302 of the CHEK2 protein (p.Glu302Asp). This variant is present in population databases (rs587780190, gnomAD 0.007%). This missense change has been observed in individual(s) with CHEK2-related cancers (PMID: 30613976, 31159747). This variant is also known as c.1035A>C p.Glu345Asp. ClinVar contains an entry for this variant (Variation ID: 128087). 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	Baylor Genetics	Mar 10, 2024	- -

CHEK2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2023

The CHEK2 c.906A>C variant is predicted to result in the amino acid substitution p.Glu302Asp. This variant was reported in an individual with male breast cancer and individuals undergoing genetic testing for hereditary cancer predisposition (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747; Table S3, referred to as c.1035A>C (p.Glu345Asp), Rizzolo et al. 2019. PubMed ID: 30613976; Table S1, Vargas-Parra et al. 2020. PubMed ID: 32906215). Experimental studies using a yeast-based system suggest this variant is semi-functional (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0067% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29099495-T-G) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128087/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CHEK2 p.Glu302Asp variant was not identified in the literature. The variant was identified in dbSNP (rs587780190) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by Invitae, Color, GeneDx, Ambry Genetics, and 3 other submitters). The variant was identified in control databases in 8 of 234,112 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 2 of 29,918 chromosomes (freq: 0.00007) and European in 6 of 101,258 chromosomes (freq: 0.00006), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Glu302 residue is 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 p.Glu302Asp variant occurs in the last codon of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C5882668:Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

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

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.76

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

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

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.41

Sift

Uncertain

0.015

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

Sift4G

Uncertain

0.013

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

Polyphen

0.95

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

Vest4

0.91

MutPred

0.81

Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);.;Gain of sheet (P = 0.1451);.;Gain of sheet (P = 0.1451);.;Gain of sheet (P = 0.1451);.;.;.;

MVP

0.80

MPC

0.054

ClinPred

0.71

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00069

dbscSNV1_RF

Benign

0.25

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