ClinVar Genomic variation as it relates to human health

This variant is denoted PALB2 c.2962C>T at the cDNA level and p.Gln988Ter (Q988X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PALB2 Gln988Ter has been reported in individuals with familial breast cancer and in the parent of a child with Fanconi anemia (Reid 2007, Hellebrand 2011, Hofstatter 2011). This variant is considered pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

This variant changes 1 nucleotide in exon 9 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in four individuals affected with breast cancer from two families and observed to segregate with disease in a mother and her two daughters (PMID: 21365267, 21618343), and this variant also has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_000013). This variant also has been detected in a parent of a child affected with Fanconi anemia, whose other parent has a different pathogenic truncation variant in PALB2 (PMID: 17200671). This variant has not been identified 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.

The p.Q988* pathogenic mutation (also known as c.2962C>T) located in coding exon 9 of the PALB2 gene, results from a C to T substitution at nucleotide position 2962. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation was described in a child with Fanconia anemia, whose clinical features included medulloblastoma, growth retardation, microcephaly, and hypoplastic thumb (Reid S et al. Nat. Genet. 2007; 39:162-4). This mutation has also been described in a patient with pre-menopausal breast cancer who had a paternal family history of pancreatic cancer (father and paternal aunt) and maternal family history of post-menopausal breast cancer (mother and two maternal aunts) (Hofstatter EW et al. Fam. Cancer 2011; 10:225-31). This mutation was also shown to segregate with disease in twin sisters with breast cancer in their forties and in their mother with bilateral breast cancer in her late fifties/early 60s (Hellebrand H et al. Hum. Mutat. 2011; 32:E2176-88). 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.

This sequence change creates a premature translational stop signal (p.Gln988*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21365267, 21618343). ClinVar contains an entry for this variant (Variation ID: 1246). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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