PALB2 NM_024675.3:c.3549C>A, Tyr1183Ter

Variant summary: PALB2 c.3549C>A (p.Tyr1183X) 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, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.9e-06 in 258634 control chromosomes. c.3549C>A has been well reported in the literature in multiple individuals affected with several cancer phenotypes such as, epithelial ovarian cancer (Ramus_2015), in bi allelic PALB2 mediated Fanconi anemia (with p.R753*, Reid_2007), breast and pancreatic cancer (Hofstatter_2011), and male breast cancer (Ding_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no detectable PALB2 protein in lymphoblastoid cells of a patient with the Fanconi anemia phenotype, thereby confirming the null allele outcome for this variant (Reid_2007). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The PALB2 c.3549C>A (p.Tyr1183*) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast, ovarian and pancreatic cancer (PMID: 26681312 (2015), 26315354 (2015), 26296701 (2015), 25099575 (2014), 21365267 (2011), 19264984 (2009)). Additionally, functional evidence suggests that this variant may impact protein function (PMID: 31757951 (2019)). The frequency of this variant in the general population, 0.000004 (1/251420 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

The p.Y1183* pathogenic mutation (also known as c.3549C>A), located in coding exon 13 of the PALB2 gene, results from a C to A substitution at nucleotide position 3549. This changes the amino acid from a tyrosine to a stop codon within exon 13. This alteration occurs at the 3' terminus of PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last four amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). The p.Y1183* mutation has been identified with a PALB2 pathogenic variant in multiple individuals with clinical features of Fanconi Anemia-N (FA-N) (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). Lymphoblastoid cells from at least one of these patients was found to have no detectable PALB2 protein (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). Truncations at this position have been reported in multiple familial breast cancer kindreds to date (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Hofstatter EW et al. Fam. Cancer. 2011 Jun;10:225-31; Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80). This alteration was also identified in 4/10030 consecutive breast cancer patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz.