ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.762G>T (p.Arg254Ser)

dbSNP: rs878854922
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000230229 SCV000289705 uncertain significance Familial cancer of breast 2024-04-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 254 of the CHEK2 protein (p.Arg254Ser). 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: 240753). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics RCV000573507 SCV000669293 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-21 criteria provided, single submitter clinical testing The p.R254S variant (also known as c.762G>T), located in coding exon 5 of the CHEK2 gene, results from a G to T substitution at nucleotide position 762. The arginine at codon 254 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, the in silico prediction for this missense impact of this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Myriad Genetics, Inc. RCV000230229 SCV004044102 likely pathogenic Familial cancer of breast 2023-06-26 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].

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