LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-14
Case ID: NM_024675.4_c.928A_G_20260614_174450
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.4:c.928A>G

PALB2  · NP_078951.2:p.(Ser310Gly)  · NM_024675.4
GRCh37: chr16:23646939 T>C  ·  GRCh38: chr16:23635618 T>C
Gene: PALB2 Transcript: NM_024675.4
Final call
Likely Benign
BS1 strong BP1 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Ser310Gly)
gnomAD AF
0.00012763305126015952 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant in PALB2 exon 4. Under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specifications for PALB2 v1.2.0, missense pathogenic variation is not yet confirmed as a mechanism of disease.
2
The variant is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.01511% (206/1,614,002 alleles), exceeding the PALB2 VCEP BS1 threshold of >0.01%, meeting BS1 at Strong strength.
3
BP1 (Supporting benign) is met per VCEP rule that applies to all PALB2 missense variants, as true missense pathogenic variants in PALB2 are thought to be exceedingly rare.
4
The gnomAD v4.1 frequency (0.01511%) does not reach the BA1 threshold (>0.1%) or the PM2 threshold (<=0.000333%). In silico predictions (SpliceAI max delta=0.02, REVEL=0.034, BayesDel=-0.732) are not used under this VCEP for missense variants per PP3/BP4 rules.
5
No case-control studies, co-segregation data, or Fanconi Anemia biallelic observations were available to assess PS4, PP1, BS2, or BS4.
6
Applying the PALB2 VCEP/ACMG combination rules: one Benign Strong criterion (BS1) plus one Benign Supporting criterion (BP1) is consistent with a Likely Benign classification per Rule 18.
Final determination: Rule18 in the Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A NM_024675.4:c.928A>G is a missense variant (p.Ser310Gly). The PALB2 VCEP v1.2.0 PVS1 decision tree applies to null variants (nonsense, frameshift, canonical splice); this missense variant does not meet PVS1 eligibility criteria.
pvs1_variant_assessment
PS1 N/A PALB2 VCEP v1.2.0 states: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.'
cspec
PS2 N/A PALB2 VCEP v1.2.0: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.'
cspec
PS3 N/A PALB2 VCEP v1.2.0 specifies that PS3 is not applicable for protein-level functional studies in this framework.
cspec
PS4 Not met No case-control study with a statistically significant odds ratio (OR>=3 or lower 95% CI >=1.5, p<=0.05) was identified for NM_024675.4:c.928A>G. The variant has been observed in clinical testing cohorts but without formal case-control analysis meeting VCEP thresholds.
clinvar
PM1 N/A PALB2 VCEP v1.2.0: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.'
cspec
PM2 Not met gnomAD v4.1 grpmax filtering allele frequency is 0.00015106 (0.01511%), which exceeds the PALB2 VCEP threshold of <=0.000333% (1/300,000) for PM2_Supporting. The variant is too common in population databases to meet this criterion.
gnomad_v4
PM5 N/A PALB2 VCEP v1.2.0: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5 in PALB2 applies only to frameshifting/truncating variants with PTCs upstream of p.Tyr1183, not missense substitutions.
cspec pm5_candidates
PM6 N/A PALB2 VCEP v1.2.0: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.'
cspec
PP1 Not assessed No co-segregation data are available for NM_024675.4:c.928A>G in affected families. No published pedigree analyses or LOD scores exist for this variant.
PP2 N/A PALB2 VCEP v1.2.0: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.'
cspec
PP3 N/A PALB2 VCEP v1.2.0: 'Missense: Do not use.' This is a missense variant. SpliceAI max delta score is 0.02 (below the 0.2 threshold), and VCEP prohibits PP3 for missense variants regardless of in silico predictions.
cspec spliceai
PP4 N/A PALB2 VCEP v1.2.0: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology and there are no features that can readily distinguish hereditary from sporadic causes.'
cspec
PP5 N/A PALB2 VCEP v1.2.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
cspec
BA1 Not met gnomAD v4.1 grpmax filtering allele frequency is 0.00015106 (0.01511%), which is below the PALB2 VCEP BA1 threshold of >0.1%.
gnomad_v4
BS1 Met gnomAD v4.1 grpmax filtering allele frequency is 0.00015106 (0.01511%), which exceeds the PALB2 VCEP BS1 threshold of >0.01%. The variant is observed at a population frequency greater than expected for PALB2-related cancer predisposition.
gnomad_v4
BS2 Not assessed The PALB2 VCEP BS2 criterion requires evaluation using the Fanconi Anemia BS2 tables (points per proband for healthy individuals with biallelic variants). No such data were available for this variant.
cspec
BS3 N/A PALB2 VCEP v1.2.0 specifies that BS3 is not applicable. Functional studies showing no damaging effect are not assessed under this framework.
cspec
BS4 Not assessed No lack-of-segregation data (LOD scores or Bayes factors) are available for NM_024675.4:c.928A>G. The PALB2 VCEP mandates quantitative co-segregation analysis for BS4 application.
cspec
BP1 Met PALB2 VCEP v1.2.0: 'Apply to all missense variants.' NM_024675.4:c.928A>G is a missense variant (p.Ser310Gly). True missense pathogenic variants in PALB2 are thought to be exceedingly rare, and this rule applies universally.
cspec
BP2 N/A PALB2 VCEP v1.2.0 deems BP2 not applicable.
cspec
BP4 N/A PALB2 VCEP v1.2.0: 'Missense: Do not use.' SpliceAI max delta is 0.02 (<=0.1), but BP4 for splice predictions is not applied to missense variants under this VCEP.
cspec spliceai
BP5 N/A PALB2 VCEP v1.2.0: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype.'
cspec
BP6 N/A PALB2 VCEP v1.2.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
cspec
BP7 N/A BP7 applies to synonymous and deep intronic variants. NM_024675.4:c.928A>G is a missense variant (p.Ser310Gly) and does not meet BP7 eligibility.
cspec
BP3 N/A Skipped per task instructions — not applicable for this variant type.
PM3 N/A Skipped per task instructions — PM3 not in ONLY ASSESS list.
PM4 N/A Skipped per task instructions — not applicable for substitution variant.
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