Submissions for variant NM_007194.4(CHEK2):c.122C>T (p.Ser41Phe)

dbSNP: rs121908694

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131220	SCV000186172	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	The p.S41F variant (also known as c.122C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 122. The serine at codon 41 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Starlova, L et al. Clin Cancer Res 2023 Aug;29(16):3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471346	SCV000550554	uncertain significance	Familial cancer of breast	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the CHEK2 protein (p.Ser41Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 126898). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000131220	SCV001339596	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 41 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Baylor Genetics	RCV000471346	SCV004217486	uncertain significance	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493441	SCV004242575	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague	RCV000114752	SCV000148650	not provided	not provided		no assertion provided	not provided