ClinVar Genomic variation as it relates to human health

The c.1592del (p.L531Cfs*30) variant in PALB2 is a frameshift variant observed to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [HR 6.1 (95% CI 2.2-17.2, p = 0.01)] (PMID: 18628482). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. The variant has been reported to segregate with breast cancer in 6 affected family members from three families (Ambry Genetics and Invitae). The minor allele frequency in gnomAD v2.1.1 is 0.001871 in the Finnish population; however, this variant known to be a Finnish founder mutation thus explaining the higher than expected population frequency (PM2_Supporting, BS1, and BA1 are not met; PMID: 17287723). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PS4, PP1_Strong, PM5_Supporting)

Observed in individuals with breast, ovarian, and prostate cancer and is considered to be a Finnish pathogenic founder variant, present in about 1% of the population (Erkko et al., 2007; Erkko et al., 2008; Heikkinen et al., 2009; Haanpaa et al., 2013; Nikkil et al., 2013; Sokolenko et al., 2015; Kotsopoulos et al., 2017; Kwong et al., 2020; Darst et al., 2021); Published functional studies demonstrate a damaging effect with regards to: DNA binding ability, homologous recombination, crosslink repair, and double stranded break repair (Erkko et al., 2007; Obermeier et al., 2015; Pauty et al., 2017; Boonen et al., 2019; Brnich et al., 2021); Case control studies suggest this variant is associated with breast cancer (Erkko et al., 2007; Erkko et al., 2008; Heikkinen et al., 2009; Southey et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26681312, 27631815, 22241545, 29922827, 24153426, 17287723, 18628482, 25619955, 25959805, 19383810, 26640152, 20003494, 28158555, 28194609, 27783279, 23941127, 28724667, 27099641, 30322717, 32546565, 33964450, 31757951, 32068069, 32853339, 32997802)

This variant deletes 1 nucleotide in exon 4 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. Functional studies have shown that this variant has reduced DNA binding, protein instability, and fails to complement PALB2-deficient cells (PMID: 17287723, 24153426, 28158555). This variant has been reported in individuals affected with breast cancer (PMID: 17287723, 18628482,22241545, 23941127, 25452441, 28724667, 27595995). This variant has been identified in 49/282888 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.

This sequence change creates a premature translational stop signal (p.Leu531Cysfs*30) 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 present in population databases (rs180177102, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17287723, 18628482, 19383810, 22241545). It is commonly reported in individuals of Finnish ancestry (PMID: 17287723, 18628482, 19383810, 22241545). ClinVar contains an entry for this variant (Variation ID: 126609). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PALB2 function (PMID: 17287723, 24153426, 26640152). For these reasons, this variant has been classified as Pathogenic.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

The c.1592delT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 1592, causing a translational frameshift with a predicted alternate stop codon (p.L531Cfs*30). This mutation is known as a Finnish founder mutation that leads to a truncated PALB2 protein deficient in homologous recombination and crosslink repair (Erkko H et al. Nature. 2007 Mar 15; 446(7133):316-9). Two studies utilizing lymphoblastoid cell lines showed that this mutation causes aberrant DNA damage response (Nikkilä J et al. Nat Commun, 2013;4:2578; Obermeier K et al. Oncogene, 2016 07;35:3796-806). One study estimated the risk of breast cancer by age 70 for females carriers of this mutation to be 40%, (95% CI, 17-77) (Erkko H et al. Clin Cancer Res. 2008 Jul 15; 14(14):4667-71). Another study found that c.1592delT was associated with a significant increased risk for breast cancer (OR 3.44) but not with increased risk for prostate or ovarian cancer (Southey MC et al. J. Med. Genet., 2016 12;53:800-811). In another study, this mutation was associated with an aggressive breast tumor phenotype compared to tumors of sporadic or familial breast cancer patients who did not carry the mutation (Heikkinen T et al. Clin. Cancer Res., 2009 May;15:3214-22). Additional studies have detected this mutation in 3/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer. (Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11), in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119), in 44/154 breast cancer families (Antoniou AC et al. N. Engl. J. Med., 2014 Aug;371:497-506), and in 1/1421 epithelial ovarian cancer patients and 0/4300 European controls (Kotsopoulos J et al. Fam. Cancer, 2017 01;16:29-34). 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.

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.