rs17879961
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2_SupportingPM5PP5
The NM_007194(CHEK2):c.470T>G(p.Ile157Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I157T) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
CHEK2
NM_007194 missense
NM_007194 missense
Scores
3
8
7
Clinical Significance
Conservation
PhyloP100: 6.65
Links
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 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 genomesCov.: 32
GnomAD3 genomes
Cov.:
32
ClinVar
Significance: Conflicting interpretations of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting interpretations
LINK: 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
T;.;T;T;.;T;.;.;D;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;.;L;L;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;.;.;.
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;.;T;T;.;.;.
Sift4G
Benign
T;T;T;T;T;.;T;D;D;.;.
Polyphen
B;B;B;B;B;B;B;.;.;.;.
Vest4
MutPred
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
MPC
0.025
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at