Submissions for variant NM_007194.4(CHEK2):c.1178C>T (p.Pro393Leu) (rs730881690)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160434	SCV000210985	uncertain significance	not provided	2016-03-30	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1178C>T at the cDNA level, p.Pro393Leu (P393L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Pro393Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. CHEK2 Pro393Leu occurs at a position that is conserved across species and is located in the protein kinase domain (Roeb 2012, Desrichard 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CHEK2 Pro393Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000576132	SCV000669239	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-07	criteria provided, single submitter	clinical testing	Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient evidence;In silico models in agreement (benign)
Invitae	RCV000704401	SCV000833349	uncertain significance	Familial cancer of breast	2019-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 393 of the CHEK2 protein (p.Pro393Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 182435). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics,Fulgent Genetics	RCV000764374	SCV000895409	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Color	RCV000576132	SCV000913581	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-01	criteria provided, single submitter	clinical testing

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