ClinVar Genomic variation as it relates to human health

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 357 of the CHEK2 protein (p.Ser357Phe). 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 breast cancer (PMID: 22419737). ClinVar contains an entry for this variant (Variation ID: 220097). 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: 22006311, 22419737). 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.

CHEK2: PM2, PS3:Supporting

This variant is denoted CHEK2 c.1070C>T at the cDNA level, p.Ser357Phe (S357F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Using alternate nomenclature, this variant has been published as CHEK2 Ser400Phe.This variant has been observed in individuals with breast cancer or serous ovarian cancer (Walsh 2011, Roeb 2012). In vivo yeast assays suggest that CHEK2 Ser375Phe results in a loss of DNA repair function (Walsh 2011, Roeb 2012). CHEK2 Ser357Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Ser357Phe occurs at a position that is conserved across species and is located in the protein kinase domain (Desrichard 2011, Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Despite some evidence suggesting pathogenicity, it is unclear whether CHEK2 Ser357Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

This missense variant replaces serine with phenylalanine at codon 357 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies in yeast have reported that this missense change impairs DNA damage repair (PMID: 22006311, 22419737). The variant has been detected in individuals affected with familial breast cancer (PMID: 22419737) and ovarian cancer (PMID: 22006311). This variant has not been identified 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.

The p.S357F variant (also known as c.1070C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1070. The serine at codon 357 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been evaluated using a yeast-based assay to assess in vivo CHEK2- mediated response to DNA damage. This group classified the p.S357F alteration as damaging based on in silico data in combination with evidence that the growth of the yeast strain after DNA damage was significantly poorer than that of wild-type CHEK2 and did not differ significantly from growth of the negative control (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21(12):2738-44). This amino acid position is highly 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.