ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3362del (p.Gly1121fs) (rs515726117)

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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 RCV000130740 SCV000185631 pathogenic Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing The c.3362delG pathogenic mutation, located in coding exon 13 of the PALB2 gene, results from a deletion of one nucleotide at position 3362, causing a translational frameshift with a predicted alternate stop codon (p.G1121Vfs*3). This mutation has been previously reported in numerous kindreds characterized by early-onset breast cancer, triple negative breast cancer, and/or pancreatic cancer (Blanco A at al. PLoS ONE. 2013 Jul;8:e67538; Janatova M et al. Cancer Epidemiol. Biomarkers Prev. 2013 Dec;22:2323-32; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Lee JEA et al. J. Pathol. 2018 May;245(1):53-60). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000114624 SCV000219007 pathogenic Familial cancer of breast 2020-08-25 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 13 of the PALB2 gene (c.3362delG), causing a frameshift at codon 1121 and creating a premature translational stop signal in the last exon of the PALB2 mRNA (p.Gly1121Valfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt a protein domain important for PALB2 protein function (PMID: 19423707). This variant is present in population databases (rs515726117, ExAC 0.002%). This variant has been observed in individuals and families affected with breast cancer (PMID: 23935836, 24136930, 24549055, 25099575, 26283626, Invitae). ClinVar contains an entry for this variant (Variation ID: 126739). This variant disrupts the WD40-repeat domain of the PALB2 protein, which is involved in BRCA2 binding (PMID: 16793542, 19423707). Several downstream truncating variants, including p.Leu1143Thrfs*14 and p.Tyr1183*, have been observed in individuals and families affected with breast, ovarian, and pancreatic cancer, and Fanconi anemia (PMID: 17200668, 17200671, 21365267, 25099575, 25452441, 26315354, Invitae). In addition, the truncating variant p.Tyr1183* that only deletes the final 4 amino acid residues results in a nonfunctional PALB2 protein (PMID: 17200671), further supporting the functional importance of the last exon. 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.
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114624 SCV000267974 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
GeneDx RCV000235614 SCV000292661 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing This deletion of one nucleotide in PALB2 is denoted c.3362delG at the cDNA level and p.Gly1121ValfsX3 (G1121VfsX3) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAG[delG]TGAC. The deletion causes a frameshift, which changes a Glycine to a Valine at codon 1121, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. PALB2 c.3362delG has been reported in individuals with breast and pancreatic cancer, some of whom also reported a family history of breast and/or pancreatic cancer (Blanco 2013, Janatova 2013, Antoniou 2014, Thompson 2015, Johns 2017). The disrupted region at the end of the gene encodes the seventh WD repeat as well as a portion of the sixth WD repeat, a region that interacts with RAD51, POLH, and BRCA2, and a region required for POLH DNA synthesis stimulation (Buisson 2014, UniProt). Furthermore, truncating pathogenic variants downstream of PALB2 c.3362delG have been identified in other breast/pancreatic cancer families and in patients with Fanconi Anemia (Rahman 2007, Reid 2007, Peterlongo 2011). We consider this variant to be pathogenic.
Color Health, Inc RCV000130740 SCV000690914 pathogenic Hereditary cancer-predisposing syndrome 2020-10-12 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 13 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 23935836, 24136930, 24549055, 25099575, 25452441, 26283626, 29431189). This variant has been identified in 1/251320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235614 SCV000888374 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193463 SCV001362312 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-25 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3362delG (p.Gly1121ValfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay or disruption of a domain important for PALB2 protein function, which are commonly known mechanisms for disease. The variant disrupts the Partner and localiser of BRCA2, WD40 domain which is involved in BRCA2 binding. A truncations downstream of this position has been classified as pathogenic by our laboratory (eg. p.Tyr1183X). The variant allele was found at a frequency of 4.1e-06 in 246142 control chromosomes. c.3362delG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Blanco_2013, Couch_2016, Janatova_2013, Thompson_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000114624 SCV001440263 pathogenic Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000114624 SCV001193402 pathogenic Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355561 SCV001550483 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Gly1121Valfs*3 variant was identified in 7 of 9236 proband chromosomes (frequency: 0.0008) from individuals or families with hereditary breast and ovarian cancer or pancreatic cancer (Antoniou 2014, Blanco 2013, Castera 2014, Couch 2015, Thompson 2015, Janatova 2013, Johns 2017). The variant was identified in dbSNP (ID: rs515726117 as “With Pathogenic allele”), ClinVar (5x as pathogenic by Ambry Genetics, Invitae, GeneDx, Color Genomics and PALB2 database and 1x as likely pathogenic by Peter MacCallum Cancer Centre), and LOVD 3.0 Database (5x). The variant was not identified in Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 1 of 246142 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 1 of 111636 chromosomes (freq: 0.000009), but not in the other populations. The p.Gly1121Valfs*3 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1121 and leads to a premature stop codon at position 1123. This alteration is predicted to result in a truncated protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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