rs17879961

chr22-28725099-A-Cchr22-28725099-A-Gchr22-28725099-A-T

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHEK2 NM_007194 missense
• Clinical Significance: Conflicting interpretations of pathogenicity criteria provided, conflicting interpretations P:1 U:2
• Conservation: PhyloP100: 6.65

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a strand (size 8) in uniprot entity CHK2_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_007194
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 32.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-28725099-A-G is described in ClinVar as [Conflicting_interpretations_of_pathogenicity, risk_factor]. Clinvar id is 5591. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Established_risk_allele=1, risk_factor=1, Pathogenic_low_penetrance=1, Likely_pathogenic=13, Uncertain_significance=9}.
• PP5: Variant 22:28725099-A>C is Pathogenic according to our data. Variant chr22-28725099-A-C is described in ClinVar as [Conflicting_interpretations_of_pathogenicity]. Clinvar id is 265327. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.470T>G	p.Ile157Ser	missense_variant	4/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.470T>G	p.Ile157Ser	missense_variant	4/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

ClinVar

Significance: Conflicting interpretations of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting interpretations

LINK:

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2015

This variant is denoted CHEK2 c.470T>G at the cDNA level, p.Ile157Ser (I157S) at the protein level, and results in the change of an Isoleucine to a Serine (ATT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, another non-conservative change at the same amino acid residue, CHEK2 Ile157Thr (I157T), has been observed in case-control studies at a higher frequency in breast and colon cancer cases than controls (Kilpivaara 2006, Suchy 2010, Desrichard 2011, Liu 2012, Han 2013). In addition, CHEK2 Ile157Thr was shown by a large meta-analysis to be associated with an increased risk of lobular breast cancer (OR>4.1) (Liu 2012). CHEK2 Ile157Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Ile157Ser occurs at a position that is highly conserved across species and is located within the FHA domain (Desrichard 2011, Roeb 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available information, we consider CHEK2 Ile157Ser to be a likely pathogenic variant. -

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.Ile157Ser variant was not identified in the literature; however, a different CHEK2 p.Ile157 variant (p.Ile157Thr) was: the Ile157 residue is located in the FHA (forkhead-associated) domain and the p.Ile157Thr variant has been suggested to be functionally deficient in dimerization and autophoshorylation activity (Cai 2009); it is uncertain whether the p.Ile157Thr variant would have a similar predicted effect on protein function. The variant was identified in dbSNP (ID: rs17879961) as “With Likely pathogenic, Pathogenic allele” and ClinVar (classified likely pathogenic by GeneDx). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Ile157 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Ser variant to the protein; this information is not very predictive of pathogenicity. 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. 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

Invitae

Jun 25, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 157 of the CHEK2 protein (p.Ile157Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 30651582). ClinVar contains an entry for this variant (Variation ID: 265327). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Ile157 amino acid residue in CHEK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

0.66

BayesDel_addAF

Pathogenic

0.26

D

BayesDel_noAF

Pathogenic

0.14

Cadd

Benign

23

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.48

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

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.97

D

M_CAP

Benign

0.057

D

MetaRNN

Uncertain

0.54

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

MetaSVM

Uncertain

0.45

D

MutationAssessor

Benign

0.85

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.58

T

PROVEAN

Benign

-2.4

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

REVEL

Uncertain

0.54

Sift

Benign

0.10

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

Sift4G

Benign

0.34

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

Polyphen

0.091

B;B;B;B;B;B;B;.;.;.;.

Vest4

0.67

MutPred

0.45

Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);.;Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);.;Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);Gain of disorder (P = 0.0085);

MVP

0.94

MPC

0.025

ClinPred

0.80

D

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.73

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17879961; hg19: chr22-29121087;