ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2515-1G>A

dbSNP: rs587776417
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000707120 SCV000836203 likely pathogenic Familial cancer of breast 2023-01-26 criteria provided, single submitter clinical testing 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. Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 21285249, 26990772, 30890586). ClinVar contains an entry for this variant (Variation ID: 582926). Disruption of this splice site has been observed in individual(s) with breast cancer and pancreatic cancer (PMID: 19264984, 21285249). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Ambry Genetics RCV001015744 SCV001176610 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing The c.2515-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 6 of the PALB2 gene. Another alteration at this same nucleotide position, c.2515G>T has been detected in patients with familial pancreatic cancer and familial breast cancer (Jones S et al. Science, 2009 Apr;324:217; Casadei S et al. Cancer Res., 2011 Mar;71:2222-9; Antoniou AC et al. N. Engl. J. Med., 2014 Aug;371:497-506). 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 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258101 SCV001434946 likely pathogenic Pancreatic cancer, susceptibility to, 3; Breast cancer, susceptibility to 2018-10-14 criteria provided, single submitter clinical testing The c.2515-1G>A variant in the PALB2 gene is predicted to disrupt a canonical splice donor site and thus alter mRNA splicing. This variant has never been reported in the general population. Therefore, this c.2515-1G>A variant in the PALB2 gene is classified as likely pathogenic.
Baylor Genetics RCV000707120 SCV004202723 likely pathogenic Familial cancer of breast 2022-08-11 criteria provided, single submitter clinical testing

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