NM_024675.3:c.3049G>A (p.Ala1017Thr) is a missense variant in PALB2, a gene for which loss of function is an established mechanism of PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia complementation group N (autosomal recessive).

This variant has been classified as a Variant of Uncertain Significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (ClinVar Variation ID: 830187) and by seven clinical laboratories.

In gnomAD v4.1, this variant is present at an overall allele frequency of 0.000081% (13/1,614,106 alleles; grpmax FAF=0.0075%), with the highest frequency in the South Asian population (0.0132%; 12/91,078 alleles). The gnomAD v2.1 frequency is 0.00040% (1/251,448 alleles).

SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL score is 0.202 and BayesDel score is -0.306, both in ranges consistent with a benign computational prediction, though in silico predictors are not used for missense variants under the PALB2 VCEP framework.

Under the PALB2 VCEP v1.2.0 framework, BP1 (Supporting) is met because all PALB2 missense variants are assigned BP1 at Supporting strength, given the very low rate of functional missense variants in PALB2. No other criteria are met under this VCEP framework.

The PM2 (Supporting) criterion is not met because the variant's gnomAD v4.1 frequency (0.00081%) exceeds the VCEP threshold of ≤0.000333%. Population frequency criteria BA1 (>0.1%) and BS1 (>0.01%) are also not met, as the grpmax FAF (0.0075%) falls below both thresholds.

PS4 is not met; although this variant has been observed in 3 cancer cases in a case-control study (Momozawa et al. 2018), no formal odds ratio or statistical significance test meeting the VCEP threshold (OR≥3, p≤0.05) has been computed for this individual variant.

Many ACMG/AMP criteria are not applicable under the PALB2 VCEP for missense variants, including PVS1 (not a null variant), PS1/PP3/BP4 (missense excluded), PM1 (missense mechanism not confirmed), PM5 (truncation/splice only), PP2 (missense mechanism not confirmed), and PS3/BS3 (not used in this VCEP).

Several criteria (PP1, BS2, BS4) remain not assessed due to absence of published co-segregation, healthy adult proband, or non-segregation data for this specific variant.

With only BP1_Supporting met and no pathogenic criteria met, this variant does not satisfy the criteria for Likely Benign (requires ≥2 benign supporting or 1 strong benign + ≥1 supporting benign). The variant remains classified as a Variant of Uncertain Significance (VUS) under the PALB2 VCEP v1.2.0 framework.