ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2515-1G>C (rs587776417)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198016 SCV000253717 likely pathogenic Familial cancer of breast 2020-09-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the PALB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs587776417, ExAC 0.009%). Disruption of this splice site has been observed in individual(s) with breast and pancreatic cancer (PMID: 19264984, 21285249). ClinVar contains an entry for this variant (Variation ID: 216006). Experimental studies have shown that disruption of this splice site disrupts mRNA splicing (PMID: 30890586,21285249). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000580827 SCV000685956 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985889 SCV001134545 likely pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Variant identified at frequency that is consistent with pathogenicity.
Ambry Genetics RCV000580827 SCV001176611 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing The c.2515-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 6 of the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are are typically deleterious in nature, however, this alteration occurs at a splice site in which <span style="font-family:open sans,helvetica neue,helvetica,arial,sans-serif">naturally occurring alternative splicing events have been described. The exact functional impact of this alteration is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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