ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2982dup (p.Ala995fs) (rs180177127)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114576 SCV000267970 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Ambry Genetics RCV000213482 SCV000273157 pathogenic Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing The c.2982dupT pathogenic mutation, located in coding exon 9 of the PALB2 gene, results from a duplication of T at nucleotide position 2982, causing a translational frameshift with a predicted alternate stop codon (p.A995Cfs*16). This alteration has been identified in multiple high-risk breast cancer patients (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Teo ZL et al. Breast Cancer Res. 2013 Feb;15:R17; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). This alteration was also identified in three high-risk patients undergoing pancreatic cancer screening; these individuals were diagnosed with breast or prostate cancer and had at least one first- or second-degree relative diagnosed with pancreatic cancer (Abe T et al. J. Clin. Oncol. 2019 05;37:1070-1080). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000114576 SCV000290857 pathogenic Familial cancer of breast 2018-06-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala995Cysfs*16) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals with breast cancer  (PMID: 17200668, 23448497, 26283626, 26534844) and pancreatic cancer (PMID: 19264984). ClinVar contains an entry for this variant (Variation ID: 126697). Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000114576 SCV000487937 likely pathogenic Familial cancer of breast 2015-12-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000213482 SCV000685997 pathogenic Hereditary cancer-predisposing syndrome 2016-12-05 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000114576 SCV001193319 pathogenic Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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