ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3323del (p.Tyr1108fs) (rs180177135)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132282 SCV000187367 pathogenic Hereditary cancer-predisposing syndrome 2018-11-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000168157 SCV000218818 pathogenic Familial cancer of breast 2019-12-19 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 12 of the PALB2 mRNA (c.3323delA), causing a frameshift at codon 1108. This creates a premature translational stop signal in the last exon of the PALB2 mRNA (p.Tyr1108Serfs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated PALB2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in a Fanconi anemia family (PMID: 17200671), and in individuals affected with breast cancer (PMID: 25452441, 26845104). ClinVar contains an entry for this variant (Variation ID: 126734). This variant is expected to delete a large portion of the WD40 domain of PALB2, which is involved in the PALB2/BRCA2 interaction. X-ray crystallography analysis of the PALB2 protein suggests that the p.Tyr1183* alteration, also located in the last exon of the protein but downstream of p.Tyr1108Serfs*16, will destabilize the PALB2 protein leading to its degradation (PMID: 19609323). Based on these data, p.Tyr1108Serfs*16 is also expected to result in PALB2 protein destabilization. For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000132282 SCV000266109 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000235326 SCV000292889 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing This deletion of one nucleotide in PALB2 is denoted c.3323delA at the cDNA level and p.Tyr1108SerfsX16 (Y1108SfsX16) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTGT[delA]CTGT. The deletion causes a frameshift which changes a Tyrosine to a Serine at codon 1108, and creates a premature stop codon at position 16 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. PALB2 c.3323delA has been observed in individuals with breast cancer and in the compound heterozygous state in an individual with Fanconi Anemia (Reid 2007, Couch 2015, Shirts 2016). Although this variant showed no significant difference in telomere length compared to controls in a genomic stability assay (Wark 2013), a medulloblastoma cell line with this variant achieved complete response to a PARP inhibitor (Smith 2015), which is consistent with the hypersensitivity to PARP inhibition observed by other PALB2 pathogenic variants (Buisson 2010, Park 2013). This variant is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235326 SCV000601783 pathogenic not provided 2015-05-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590634 SCV000699590 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The PALB2 c.3323delA (p.Tyr1108Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PALB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.3549C>A / p.Tyr1183X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121760 control chromosomes. This variant has been reported in multiple affected individuals including BrC patients and FA-N patients (e.g., Antoniou_NEJM_2014; Reid_NG_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000168157 SCV000785696 pathogenic Familial cancer of breast 2017-11-08 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000114618 SCV000993424 pathogenic Fanconi anemia, complementation group N 2018-06-28 criteria provided, single submitter research ACMG codes: PVS1, PM2, PM3, PP5
Color RCV000132282 SCV001352971 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000235326 SCV001193395 pathogenic not provided 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz.

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