ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3256C>T (p.Arg1086Ter) (rs587776527)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212825 SCV000211531 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted PALB2 c.3256C>T at the cDNA level and p.Arg1086Ter (R1086X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in families presenting with breast, ovarian and/or pancreatic cancers (Jones 2009, Grant 2013, Norquist 2015, Ramus 2015, Thompson 2015, Frey 2017, Zhang 2017), and is considered pathogenic.
Invitae RCV000168017 SCV000218669 pathogenic Familial cancer of breast 2020-10-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1086*) 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 individual(s) affected with pancreatic cancer (PMID: 19264984, 23561644, 25356972), breast cancer (PMID: 26283626, 26845104), and ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 126729). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000160853 SCV000266108 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000168017 SCV000267973 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Ambry Genetics RCV000160853 SCV000538169 pathogenic Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing The p.R1086* pathogenic mutation (also known as c.3256C>T), located in coding exon 12 of the PALB2 gene, results from a C to T substitution at nucleotide position 3256. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been reported in multiple unrelated families with breast, ovarian and pancreatic cancer histories (Jones S et al. Science. 2009 Apr;324:217; Grant RC et al. Hum. Genomics. 2013 Apr;7:11; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). Another large case-control study identified this alteration in 1/1996 breast cancer cases and 1/1998 non-cancer controls, with the one case having bilateral breast cancer at 44 years of age (Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Li JY et al. Int. J. Cancer. 2019 Jan;144(2):281-289). 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.
Color Health, Inc RCV000160853 SCV000686021 pathogenic Hereditary cancer-predisposing syndrome 2020-11-06 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 12 of the PALB2 gene, creating a 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: 28724667, 29752822, 32566746) or pancreatic cancer (PMID: 19264984, 23561644, 25356972). This variant has been identified in 5/251482 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.
Illumina Clinical Services Laboratory,Illumina RCV000778458 SCV000914709 pathogenic PALB2-Related Disorders 2018-04-25 criteria provided, single submitter clinical testing The PALB2 c.3256C>T (p.Arg1086Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, it has been reported in a heterozygous state in at least eleven individuals with cancer, including five with pancreatic cancer, three with breast cancer (one bilateral), and one with ovarian cancer (Jones et al. 2009; Grant et al. 2013; Thompson et al. 2015; Zhen et al. 2015; Norquist et al. 2016; Susswein et al. 2016; Sun et al. 2017). Five of these individuals had a family history of cancer. Although the p.Arg1086Ter variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Control data are unavailable for this variant, which is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the available evidence, the p.Arg1086Ter variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030644 SCV001193674 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
OMIM RCV000114612 SCV000021464 risk factor Pancreatic cancer 3 2009-04-10 no assertion criteria provided literature only
Leiden Open Variation Database RCV000114612 SCV001193379 pathogenic Pancreatic cancer 3 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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