NM_024675.4:c.509_510delGA (p.Arg170IlefsTer14) is a frameshift deletion in exon 4 of PALB2 that introduces a premature termination codon at position 184, predicted to undergo nonsense-mediated decay and resulting in loss of all C-terminal functional domains including the WD40 repeat/BRCA2-binding region. Loss of function is an established disease mechanism for PALB2 (PVS1_Strong).¹ The variant is significantly enriched in breast cancer cases compared to population controls. Noskowicz et al. (2014) identified the variant in 10/3,924 (0.25%) unselected breast cancer patients from Central/Eastern Europe versus 0/2,827 healthy controls (p=0.007). Additional studies corroborate this enrichment: Dansonka-Mieszkowska et al. (2010) found the variant in 6/987 (0.6%) cancer cases versus 1/1,310 controls; Kluska et al. (2017) detected it in 0.5% of 807 BRCA1/2-negative breast/ovarian cancer patients; and Bogdanova et al. (2011) identified it in 2/203 bilateral breast cancer patients. Collectively, these studies meet PS4 at Strong strength.² The premature termination codon at position 184 lies upstream of p.Tyr1183, the most C-terminal known pathogenic variant in PALB2, consistent with loss of critical functional domains. Under the PALB2 VCEP, this satisfies PM5_Supporting. The variant is present at low frequency in gnomAD (v4.1: 30/1,614,006, 0.00186%; v2.1: 9/251,446, 0.00358%), with no homozygotes. This frequency exceeds the PALB2 VCEP PM2_Supporting threshold (≤0.000333%) and remains well below benign population thresholds (BA1 >0.1%, BS1 >0.01%), providing neither pathogenic nor benign population evidence.³ SpliceAI predicts no cryptic splice effect (max delta = 0.00). No co-segregation or non-segregation data are available. No functional studies specific to this variant have been published.⁴