22-28725090-A-G

Position:

chr22-28725090-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_007194.4(CHEK2):c.479T>C(p.Ile160Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I160K?) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 6.65

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_pathogenic. Variant got 6 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].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.479T>C	p.Ile160Thr	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.479T>C	p.Ile160Thr	missense_variant	4/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251410

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135892

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 08, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 160 of the CHEK2 protein (p.Ile160Thr). 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 prostate cancer (PMID: 32923906). This variant is also known as p.Ile203Thr. ClinVar contains an entry for this variant (Variation ID: 186900). 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065). 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	Oct 05, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 19, 2023	The p.I160T variant (also known as c.479T>C), located in coding exon 3 of the CHEK2 gene, results from a T to C substitution at nucleotide position 479. The isoleucine at codon 160 is replaced by threonine, an amino acid with similar properties. This variant was identified in 1/317 men in a metastatic prostate cancer cohort undergoing hereditary cancer genetic testing (Boyle JL et al. JCO Precis Oncol, 2020 Mar;4:). This alteration was also identified in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648) and was reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 02;82:615-631). This alteration was also reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). Of note, this alteration is also known as c.608T>C in published literature. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2021	This missense variant replaces isoleucine with threonine 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). A functional study has shown this variant to have damaging effect on CHEK2 protein function (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251410 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:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 20, 2024

Variant summary: CHEK2 c.479T>C (p.Ile160Thr) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.479T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and Prostate Cancer, without evidence for causality. One publication reports experimental evidence indicating that the variant impairs DNA-damage repair in a yeast-based assay (Delimitsou_2019) and another indicates it is functionally impaired (Stolarova_2023), however additional evidence is needed to allow unequivocal conclusions about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 31398194, 32923906, 30851065, 21153778, 37449874). ClinVar contains an entry for this variant (Variation ID: 186900). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: large decrease in growth rate after DNA damage compared to wildtype (Delimitsou 2019); This variant is associated with the following publications: (PMID: 31398194, 30851065, 21153778) -

Familial ovarian cancer

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CHEK2 p.Ile160Thr variant was not identified in the literature. The variant was identified in dbSNP (ID: rs72552323) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Counsyl, GeneDx and Color). The variant was identified in control databases in 1 of 246208 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111664 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Although the p.Ile160 residue is not conserved in mammals and other organisms, 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.079

MetaRNN

Pathogenic

0.86

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;H;H;H;.;H;H;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0050

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

Polyphen

0.99

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

Vest4

0.81

MutPred

0.64

Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);.;Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);.;Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);

MVP

1.0

MPC

0.15

ClinPred

0.99

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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