ClinVar Genomic variation as it relates to human health

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 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A function study has reported that this truncated variant protein disrupted PALB2 function in a homology-directed DNA repair assay (PMID: PMID: 31757951). This variant has been observed in six individuals affected with breast cancer (PMID: 21285249, 23935836, 31446535), one of whom was affected with early-onset, triple-negative breast cancer with family history of breast and pancreatic cancer (PMID: 23935836) and three others had family history of breast cancer (PMID: 31446535). This variant has been observed in compound heterozygous state with the deletion of PALB2 exons 1-10 in an individual affected with Fanconi anemia (PMID: 17200672, 17924555). Fibroblasts from this individual lacked the full-length PALB2 protein and exhibited hypersensitivity and loss of DNA damage responses after mitomycin C treatment (PMID: 17200672). 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.

This sequence change creates a premature translational stop signal (p.Tyr551*) 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 and/or ovarian cancer and/or Fanconi anemia (PMID: 17200672, 21285249, 23935836). ClinVar contains an entry for this variant (Variation ID: 1243). For these reasons, this variant has been classified as Pathogenic.

The p.Y551* pathogenic mutation (also known as c.1653T>A), located in coding exon 4 of the PALB2 gene, results from a T to A substitution at nucleotide position 1653. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. In one study, this mutation was found to be functionally abnormal in both a homology-directed DNA repair (HDR) assay and a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This alteration was also found to be functionally abnormal in another HDR assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This mutation has previously been reported in multiple individuals with personal history of breast cancer and family history of breast and/or pancreatic cancer (Casadei S et al. Cancer Res. 2011 Mar; 71(6):2222-9; Blanco A et al. PLoS ONE 2013; 8(7):e67538; Cerretini R et al. Breast Cancer Res Treat, 2019 Dec;178:629-636) and in trans with a partial PALB2 gene deletion in an individual with Fanconi anemia (Xia B et al Nat. Genet. 2007 Feb;39(2):159-61). 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.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jones et al., 2009; Casadei et al., 2011; Blanco et al., 2013; Hu et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25583207, 27829436, 31446535, 19264984, 25525159, 21285249, 24141787, 23038782, 20871615, 24870022, 23935381, 21165770, 23935836, 31589614, 29922827, 17200672, 33471991, 31636395, 31757951)

Data included in classification: PVS1_vstr: Truncating variant predicted to undergo NMD PM5_sup: Truncating variant with premature stop codon upstream of p.Tyr1183 PM2_sup: Absent from gnomAD PM3_mod: Xia et al 2007, confirmed in trans in patient with Fanconi Anaemia (2/3 clinical features) Data not included in classification: 2 breast cancer cases and 0 controls (Casadei et al., 2011; PMID: 21285249) 2 bilateral breast cancer patients in Argentina (Cerretini et al., 2019; PMID 31446535) 1 family in Spain, only proband confirmed to carry the variant (Blanco et al., 2014; PMID: 23935836) Evidence of loss of function from Boonen et al, 2019 HDR assay and PARP sensitivity assays

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