The PALB2 c.721A>G (p.Asn241Asp) missense variant has an allele frequency of 0.63% in the African/African American population in gnomAD v4.1 (472/75,032 alleles) with 3 homozygous individuals observed. The grpmax filtering allele frequency of 0.58% exceeds the PALB2 VCEP BA1 threshold of >0.1%, meeting stand-alone benign criteria.¹ The grpmax filtering allele frequency of 0.58% in gnomAD v4.1 far exceeds the PALB2 VCEP BS1 threshold of >0.01%, providing strong benign evidence. This allele frequency is inconsistent with a highly penetrant pathogenic variant for PALB2-related cancer predisposition.² BP1 (supporting benign) is met per PALB2 VCEP v1.2.0, which applies to all PALB2 missense variants given that true missense pathogenic variants are thought to be exceedingly rare in this gene based on published and unpublished functional studies.³ This variant has been classified as Benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (expert panel review) and is reported as Benign by 9 clinical laboratories and Likely benign by 8 clinical laboratories in ClinVar (VariationID: 126765).⁴ SpliceAI predicts no splice impact (max delta score 0.00). REVEL score is 0.013 and BayesDel score is -0.834, consistent with a benign in silico profile, though these predictors are not used for PALB2 missense variants per VCEP guidance.⁵ PVS1, PS1, PS3, PM1, PP2, and PP3 are not applicable to this missense variant per PALB2 VCEP v1.2.0. PS4, PM2, PP1, and BS4 are not met due to absence of required evidence. Full-text verification of cited publications was attempted but the retrieved full-text files contained only Sci-Hub interface content rather than actual paper text; citation verification was limited to abstracts.⁶ Applying the PALB2 VCEP v1.2.0 final classification rules: BA1 (stand-alone benign) is met, which alone satisfies Rule 17 (>=1 Stand Alone Benign) for a Benign classification. Additionally, BS1 (strong benign) and BP1 (supporting benign) are met, further supporting the benign interpretation.⁷