PALB2 NM_024675.3:c.514_517del, Ser172GlyfsTer4

Variant summary: PALB2 c.514_517delTCTG (p.Ser172GlyfsX4) 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. The variant was absent in 251460 control chromosomes (gnomAD). c.514_517delTCTG has been reported in the literature in at least one young patient with HER2-amplified breast cancer, a patient with prostate cancer and a breast cancer patient (Eccles_2016, Momozawa_2020, Zhou_2020). These data indicate that the variant may be associated with disease. In a cell based functional assays, compared to wild-type the variant was found to have a relative HR (homologous recombination) efficiency of 8.55% and in PARPi sensitive assays, a PARPi resistance of 13.87% (Boonen_2019). Two other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant deletes 4 nucleotides 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. A functional study reported that a protein frameshift variant at serine 172 abolished stable protein expression and PALB2 function in a homology-directed repair assay (PMID: 31757951). This variant has been reported in an individual affected with breast cancer (PMID: 26681682) and in a breast cancer case-control study in 1/16501 cases and absent in 5890 unaffected individuals (PMID: 32339256). This variant also has been reported in a prostate cancer case-control study in 1/7636 cases and absent in 12366 unaffected individuals (PMID: 31214711). 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. Based on the available evidence, this variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Ser172Glyfs*4) 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 variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 461007). For these reasons, this variant has been classified as Pathogenic.