NM_024675.3:c.82T>A (p.Tyr28Asn) is a missense variant in PALB2. It is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting per PALB2 VCEP v1.2.0 (allele frequency ≤ 0.000333%).

BP1_Supporting is applied as the PALB2 VCEP v1.2.0 assigns this criterion to all missense variants in PALB2, given that PALB2 has a low rate of functionally impactful missense variants and true pathogenic missense variants are thought to be exceedingly rare.

In silico predictors are not applied (PP3/BP4 not used for missense variants per VCEP). REVEL score is 0.219 and BayesDel score is 0.039. SpliceAI predicts no splice impact (max delta = 0.00).

This variant has been reported in ClinVar (ID 410148) as Uncertain Significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP and by 3 clinical laboratories. No case-control studies, co-segregation data, or functional studies specific to this variant were identified.

PVS1, PS1, PS3, PM1, PM5, PP2, PP3, PP4, PP5, BS3, BP2, BP4, BP5, BP6, and BP7 are not applicable per PALB2 VCEP v1.2.0 rules, predominantly because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2. PS2, PS4, PM6, PP1, BA1, BS1, BS2, and BS4 are not met due to absence of qualifying evidence.

With PM2_Supporting (1 pathogenic supporting criterion) and BP1_Supporting (1 benign supporting criterion) in a VCEP framework with no other met criteria, the evidence is balanced between benign and pathogenic signals. The variant is classified as Uncertain Significance per the ACMG/AMP combining rules (Rule 31: ≥1 benign supporting + ≥1 pathogenic supporting → VUS with conflicting evidence). This is consistent with the ClinGen Expert Panel classification.