ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2586+1_2586+2delinsTA

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002426092 SCV002743960 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-10 criteria provided, single submitter clinical testing The c.2586+1_2586+2delGTinsTA intronic variant, located in intron 6 of the PALB2 gene, results from a deletion of GT and the insertion of TA at nucleotide positions 2586+1 to 2586+2. These nucleotide positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003101993 SCV003330746 likely pathogenic Familial cancer of breast 2022-06-29 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 6 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with PALB2-related conditions. Studies have shown that disruption of this splice site results in multiple RNA products and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.

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