ClinVar Genomic variation as it relates to human health

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21165770, 25452441, 28281021, 23341105, 25263539, 26556299, 2985019, 26845104, 25099575, 28152038, 28873162, 33646313, 32885271, 32427313, 31636395, 17200671)

This sequence change creates a premature translational stop signal (p.Tyr1108Serfs*16) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the PALB2 protein. 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 and Fanconi anemia (PMID: 17200671, 25452441, 26845104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 126734). 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 does not substantially affect PALB2 function (PMID: 23341105). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 21365267, 22241545, 26315354). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant deletes 1 nucleotide in exon 12 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 breast cancer (PMID: 17200671, 25099575, 25452441, 26845104, 28281021). 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 variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This frameshift variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with breast cancer (PMIDs: 25452441 (2015), 26845104 (2016), 32427313 (2020), and 32885271 (2021)). A functional study found that this variant was deficient in homology-directed DNA repair activity (PMID: 31636395 (2020)). Based on the available information, this variant is classified as pathogenic.

The c.3323delA (p.Y1108Sfs*16) alteration, located in exon 12 (coding exon 12) of the PALB2 gene, consists of a deletion of one nucleotide at position 3323, causing a translational frameshift with a predicted alternate stop codon after 16 amino acids. This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 5% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in a parent of an individual with Fanconi anemia type N (Reid, 2007). This variant has also been reported in multiple individuals with hereditary breast cancer (Antoniou, 2014; Couch, 2015; Shirts, 2016; Crawford, 2017; Palmer, 2020; Lerner-Ellis, 2021). Other truncating variants downstream have been observed in individuals with a personal and/or family history that is consistent with PALB2-related disease (Ambry internal data). This alteration was found to be functionally abnormal in a homology-directed DNA repair (HDR) assay (Wiltshire, 2020). Based on the available evidence, this alteration is classified as pathogenic.

ACMG codes: PVS1, PM2, PM3, PP5

Variant summary: PALB2 c.3323delA (p.Tyr1108SerfsX16) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Tyr1183X). The variant was absent in 251818 control chromosomes. c.3323delA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Antoniou_2014, Couch_2016, Crawford_2017, Reid_2007). These data indicate that the variant is likely to be associated with disease. Multiple clinical diagnostic laboratories and the LOVD database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The c.3323del variant identified in PALB2 has previously been reported in the parent of an individual with Fanconi anemia type N (PMID: 17200671), and in multiple individuals with hereditary breast cancer [PMID: 25099575, 25452441, 32427313, 32885271]. The c.3323del variant has been deposited in ClinVar [ClinVar ID: 126734] as Pathogenic by multiple submitters. This variant is observed in 8 alleles in population databases (~0.002% MAF with 0 homozygote in gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.3323del variant, located in exon 12 of this 13-exon gene, is predicted to result in a frameshift variant with premature incorporation of a termination codon (p.Tyr1108SerfsTer16). While this alteration is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5% of the PALB2 protein (79 amino acids). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic [PMID: 17200668, 19609323, 21365267, 22241545, 26315354]. Based on available evidence this c.3323del, p.(Y1108SfsTer16) variant identified in PALB2 is classified as Pathogenic.

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

The PALB2 p.Tyr1108Serfs*16 variant was identified in 5 of 7044 proband chromosomes (frequency: 0.0007) from individuals or families with fanconi anemia and hereditary breast and ovarian cancer (Reid 2007, Couch 2015, Shirts 2016, Antoniou 2014). The variant was identified in dbSNP (rs180177135) as “with pathogenic allele”, ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Counsyl and 4 other submitters) and LOVD 3.0 (observed 5x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3323del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1108 and leads to a premature stop codon at position 1123. 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 hereditary breast and ovarian cancer 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.