rs730881697

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The ENST00000404276.6(CHEK2):c.277T>C(p.Trp93Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,784 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W93C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CHEK2
ENST00000404276.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.92

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 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.277T>C	p.Trp93Arg	missense_variant	2/15	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.277T>C	p.Trp93Arg	missense_variant	2/15	1	NM_007194.4	ENSP00000385747	P2	O96017-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251224

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135814

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

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	Color Diagnostics, LLC DBA Color Health	Oct 03, 2023	This missense variant replaces tryptophan with arginine at codon 93 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). This variant has been shown to impact function in a yeast DNA repair assay (PMID: 30851065) and in a kinase assay (PMID: 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 32885271, 37449874), and in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000228). This variant has been identified in 1/251224 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 08, 2024	The p.W93R variant (also known as c.277T>C), located in coding exon 1 of the CHEK2 gene, results from a T to C substitution at nucleotide position 277. The tryptophan at codon 93 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in an individual diagnosed with breast cancer at age 61 and 71 (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This variant behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 28, 2024	The p.Trp93Arg variant is observed in 1/113,576 (0.0009%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Trp93Arg variant is novel (not in any individuals) in 1kG. There is a moderate physicochemical difference between tryptophan and arginine. The p.Trp93Arg missense variant is predicted to be damaging by both SIFT and PolyPhen2. For these reasons, this variant has been classified as Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33298767, 32885271, 33471991, 37449874, 22419737, 19782031, 34326862, 30851065) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 29, 2017	- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CHEK2 p.Trp93Arg variant was not identified in the literature. The variant was identified in dbSNP (rs730881697) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by Invitae, Color, Ambry Genetics and 2 other submitters). The variant was identified in control databases in 1 of 246,184 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111,672 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. A yeast-based functional assay showed that the variant had a damaging effect on cell function (Delimitsou 2019). The p.Trp93 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 variant occurs outside of the splicing consensus sequence and 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 93 of the CHEK2 protein (p.Trp93Arg). This variant is present in population databases (rs730881697, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 182447). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

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

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

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

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-12

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

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.81

MutPred

0.70

Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);

MVP

0.97

MPC

0.19

ClinPred

1.0

GERP RS

5.4

Varity_R

0.98

gMVP

0.63

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