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.
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
GnomAD3 genomesCov.: 32
Submissions by phenotype
|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 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 â€šÃ„ÃºWith Likely pathogenic, Pathogenic alleleâ€šÃ„Ã¹ 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 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. -|
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