rs575910805

Positions:

chr22-28725089-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM5BP4_ModerateBP6

The NM_007194.4(CHEK2):c.480A>G(p.Ile160Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,614,166 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 Conflicting classifications of pathogenicity (no stars). 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18B:2

Conservation

PhyloP100: 0.0140

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 Uncertain_significance. Variant got 1 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=0.17039022).

BP6

Variant 22-28725089-T-C is Benign according to our data. Variant chr22-28725089-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128077.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.480A>G	p.Ile160Met	missense_variant	4/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.480A>G	p.Ile160Met	missense_variant	4/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152230

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251414

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135890

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:

0.000784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000670

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000707

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74502

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:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000644

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:18Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2023	Published functional studies are inconclusive: partial to no impact on response to DNA damage and growth rate, expression levels similar to wild type, and phosphorylation of Thr68 when irradiated similar to wild type (Roeb et al., 2012; Delimitsou et al., 2019; Wagener et al., 2022); Observed in individuals with breast cancer (Dufault et al., 2004; Mohamad et al., 2015; Tsai et al., 2019; Akcay et al., 2020; da Costa e Silva Carvalho et al., 2020; Moradian et al., 2021; Andrikopoulou et al., 2022; Zografos et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.609A>G or p.Ile203Met; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22419737, 15095295, 25629968, 28553140, 30303537, 32546565, 27153395, 30851065, 31159747, 31296309, 30374176, 32039725, 32900738, 33558524, 32658311, 33471991, 35127508, 28779002, 35772246, 36468172, 25186627, 19782031, 36011273) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CHEK2 p.Ile160Met variant was identified in 4 of 2906 proband chromosomes (frequency: 0.001) from German and Malaysian individuals or families with BRCA1/2 negative HBOC or breast cancer and was identified in 1 of 1540 control chromosomes (freq: 0.001) from healthy individuals (Dufault 2004, Mohamad 2015). Functional analyses using a yeast based assay to assess in vivo CHEK2 mediated response to DNA damage showed the variant had a partial response to DNA damage (Roeb 2012). In this study, the variant co-occurred with CHEK2 p.G167R which was found to have no response to DNA damage; further, segregation studies showed the p.Ile160Met was carried by the affected father diagnosed with breast cancer and his elderly unaffected sister. The variant was also identified in the following databases: dbSNP (ID: rs575910805) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: uncertain significance by GeneDx and Ambry Genetics, and likely benign by Invitae), Clinvitae (3x), Cosmic (1x in a Ewings sarcoma tumour), and was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 31 of 277194 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). Observations by population include, European Non-Finnish in 7 of 126678 chromosomes (freq. 0.00006) and South Asian in 24 of 30782 chromosomes (freq. 0.0008); it was not seen in the East Asian, Other, Latino, Ashkenazi Jewish, and European Finnish populations. The p.Ile160 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of Met to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 24, 2023	This missense variant replaces isoleucine with methionine at codon 160 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies showed the variant has intermediate to wild-type ability to complement yeast rad53 mutant (PMID:22419737, 30851065). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 15095295, 22419737, 25629968, 27153395, 32039725, 33558524). This variant has been identified in 31/282820 chromosomes (24/30612 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). In a large breast cancer case-control study, this variant has been observed in 7/60466 cases, 4/53461 unaffected controls (OR=1.547; 95%CI 0.453 to 5.286; p-value=0.557; Leiden Open Variation Database DB-ID CHEK2_000203 (PMID: 33471991). In summary, this is a variant of unknown impact on function that has been observed in affected individuals as well as in the general population. 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	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 20, 2022	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	Oct 19, 2021	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 28, 2023	Variant summary: CHEK2 c.480A>G (p.Ile160Met) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 252594 control chromosomes, predominantly at a frequency of 0.00078 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.5 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 CHEK2 and highly homologous pseudogenes.. c.480A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Dufault_2004, Roeb_2012, Mohamad_2015, Tung_2015, Maxwell_2016, Delimitsou_2019, Girard_2019, Tsai_2019, Carvalho_2020, Akcay_2021, Dorling_2021, Moradian_2021, Andrikopoulou_2022, Zografos_2022) but it was also reported in controls (e.g. Mohamad_2015, Dorling_2021). Co-occurrences with a likely pathogenic variant were reported in two of these studies (CHEK2 c.499G>A, p.Gly167Arg; Roeb_2012, Tung_2015). Segregation analysis in one of these studies (Roeb_2012) detected the two variants in compound heterozygosity in two affected sisters and c.480A>G alone in two of their unaffected sisters (ages 51 and 53yrs), their affected father and their elderly unaffected aunt (96yrs). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Experimental evidence evaluating an impact on protein function demonstrated the variant has a partial DNA damage response through usage of an in vivo yeast-based assay (Roeb_2012). However, a more recent study also utilizing an in vivo yeast-based assay, concluded the variant to be benign/functional (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22419737, 25186627, 15095295, 25629968, 27153395, 30851065, 30374176, 30303537, 31159747, 32039725, 32658311, 33471991, 33558524, 35127508, 36011273). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=12) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Familial cancer of breast

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	research	Center of Medical Genetics and Primary Health Care	Apr 08, 2020	ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: FHA functional domain (Y156-218V aa) as phosphopeptide recognition site. Hot-spot has 18 non-VUS coding variants (12 pathogenic and 6 benign), pathogenicity = 66.7%, proximity score 7.639> threshold 2.472. PP2 Pathogenic Supporting: 30 out of 48 non-VUS missense variants in gene CHEK2 are pathogenic = 62.5% > threshold of 51.0%, and 308 out of 1,604 clinically reported variants in gene CHEK2 are pathogenic = 19.2% > threshold of 12.0%. PP3 Pathogenic Supporting: 8 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs 3 benign predictions from DEOGEN2, EIGEN and PrimateAI. PP4 Pathogenic Supporting: Patient was diagnosed with BC at the age 36 yo with family history of breast cancer. Meantime, this variant has been shown to have a partial response to DNA damage in an in vivo functional assay (Roeb 2012). CHEK2 Ile160Met has been observed in individuals with breast and/or ovarian cancer (Dufault 2004, Mohamad 2015, Maxwell 2016). Therefore, this variant was classified as a Variant of Unknown Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 24, 2020	- -

Li-Fraumeni syndrome 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 30, 2023

- -

CHEK2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

The CHEK2 c.480A>G variant is predicted to result in the amino acid substitution p.Ile160Met. This variant has been reported in individuals with suspected hereditary breast and/or ovarian cancer with conflicting interpretations of likely benign and uncertain (Dufault et al. 2004. PubMed ID: 15095295; Mohamad et al. 2015. PubMed ID: 25629968; Maxwell et al. 2016. PubMed ID: 27153395, Table S5; Girard et al. 2018. PubMed ID: 30303537, Table S3; Tsai et al. 2018. PubMed ID: 30374176; Tsaousis et al. 2019. PubMed ID: 31159747, Table S5; da Costa et al. 2020. PubMed ID: 32039725). It has been reported in at least one control individual in a cohort study (Mohamad et al. 2015. PubMed ID: 25629968). Experimental studies in yeast are conflicting (Roeb et al. 2012. PubMed ID: 22419737; Delimitsou et al. 2019. PubMed ID: 30851065). It is reported in 0.078% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain significance by the vast majority of laboratories in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128077/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 25, 2020

- -

CHEK2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

0.13

Eigen_PC

Benign

0.029

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.17

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

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.3

M;M;M;M;.;M;M;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.7

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

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.98

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

Vest4

0.58

MVP

0.95

MPC

0.14

ClinPred

0.38

GERP RS

-0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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