ClinVar Genomic variation as it relates to human health

Frameshift 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Ramus 2015, Singh 2018, Petridis 2019, Lerner-Ellis 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26315354, 29470806, 32885271, 31263054)

The c.2488delG pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2488, causing a translational frameshift with a predicted alternate stop codon (p.E830Sfs*21). This mutation has been identified in an unaffected 45 year old woman with a family history of ovarian cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107:). This mutation was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). 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 variant deletes 1 nucleotide in exon 5 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. This variant has been reported in individuals affected with ovarian cancer in the literature (PMID: 26315354). This variant has been identified in 1/251294 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 variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This sequence change creates a premature translational stop signal (p.Glu830Serfs*21) 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 (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with family history of ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 230859). For these reasons, this variant has been classified as Pathogenic.

The p.Glu830SerfsX21 variant in PALB2 has been reported in at least 3 individuals with breast or ovarian cancer (Ramus 2015 PMID: 26315354, Singh 2018 PMID: 29470806, Lerner-Ellis 2020 PMID: 32885271). It has also been identified in 0.02% (1/4836) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 230859). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 830 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PALB gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominan hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.

The PALB2 p.Glu830Serfs*21 variant was identified in 1 of 6472 proband chromosomes (frequency: 0.0002) from individuals or families with epithelial ovarian cancer (Ramus 2015). The variant was also identified in dbSNP (ID: rs876658813) as "With Pathogenic allele" and ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and Color). The variant was not identified in LOVD 3.0 or the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.2488del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 830 and leads to a premature stop codon at position 850. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.