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

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

NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant in PALB2, a gene in which primarily truncating variants are known to cause disease and missense pathogenic variation is not yet confirmed as a disease mechanism (VCEP v1.2.0).

The variant is present in gnomAD v4.1 at an overall allele frequency of 0.01276% (206/1,614,002 alleles, 0 homozygotes) with a grpmax filtering AF of 0.015106% in the European (non-Finnish) population. This exceeds the PALB2 VCEP BS1 threshold of >0.01%, supporting a benign interpretation at Strong strength.

SpliceAI predicts no significant splice impact (max delta score = 0.02), consistent with a missense change without cryptic splice effects.

REVEL score is 0.034 and BayesDel score is -0.732, consistent with a benign in silico profile, though computational predictors have not been validated for PALB2 missense variant functional outcome per the VCEP.

BP1 (Supporting) is applied per the PALB2 VCEP, which assigns this code to all missense variants given the very low prior probability that PALB2 missense variants are pathogenic.

Combining BS1 (Strong benign) with BP1 (Supporting benign) yields a classification of Likely Benign per the ACMG/AMP combination rules adopted by the PALB2 VCEP (Rule 20: ≥1 Benign Strong criterion).

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	PVS1 is restricted to null variants (nonsense, frameshift, canonical splice ±1/2, initiation codon, full gene deletion) per the PALB2 VCEP PVS1 Decision Tree. NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant and does not qualify.	cspec pvs1_variant_assessment
PS1	N/A	PALB2 VCEP restricts PS1 to splicing variants via the PALB2 PS1 Splicing table; missense variants are explicitly excluded per VCEP instruction: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.'	cspec
PS2	N/A	PALB2 VCEP states PS2 is not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.'	cspec
PS3	N/A	PALB2 VCEP states PS3 is not applicable.	cspec
PS4	Not met	PALB2 VCEP requires case-control studies with p≤0.05 AND (OR≥3 OR lower 95% CI≥1.5). No published case-control data meeting this statistical threshold has been identified for NM_024675.4:c.928A>G.	cspec
PS5	N/A	PS5 is not a standard ACMG/AMP criterion. The equivalent criterion PP5 is designated 'Not Applicable for this VCEP' per the PALB2 VCEP.	cspec
PM1	N/A	PALB2 VCEP states PM1 is not applicable: 'Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.'	cspec
PM2	Not met	PALB2 VCEP assigns PM2_Supporting when gnomAD v4 frequency ≤0.000333% (1/300,000). The grpmax filtering AF in gnomAD v4.1 is 0.015106% (0.00015106), which exceeds this threshold. PM2 is not met.	gnomad_v4 cspec
PM5	N/A	PALB2 VCEP states: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5_Supporting is restricted to frameshifting/truncating variants with PTC upstream of p.Tyr1183 and qualifying splice variants.	cspec pm5_candidates
PM6	N/A	PALB2 VCEP states PM6 is not applicable: 'Informative de novo occurrences have not yet been observed.'	cspec
PP1	Not met	No segregation data (LOD score or co-occurrence in affected relatives) has been published for NM_024675.4:c.928A>G. PALB2 VCEP requires quantitative co-segregation analysis.	cspec
PP2	N/A	PALB2 VCEP states PP2 is not applicable: 'Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.'	cspec
PP3	N/A	PALB2 VCEP states for PP3: 'Missense: Do not use.' The splicing sub-rule (SpliceAI ≥0.2) does not apply because SpliceAI max delta is 0.02 and the VCEP explicitly excludes missense variants from PP3.	cspec spliceai
PP4	N/A	PALB2 VCEP states PP4 is not applicable: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology.'	cspec
PP5	N/A	PALB2 VCEP states PP5 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	PALB2 VCEP requires grpmax Filtering AF >0.1% in gnomAD v4. The observed grpmax FAF in gnomAD v4.1 is 0.015106%, which does not exceed the 0.1% threshold.	gnomad_v4 cspec
BS1	Met	PALB2 VCEP assigns BS1 (Strong) when grpmax Filtering AF >0.01% in gnomAD v4. The grpmax FAF in gnomAD v4.1 is 0.015106%, which exceeds the VCEP threshold. The variant is observed in 206/1,614,002 alleles (AF=0.01276%) in gnomAD v4.1, predominantly in the European (non-Finnish) population (201/1,179,992 alleles).	gnomad_v4 cspec
BS2	Not met	PALB2 VCEP BS2 applies to Fanconi Anemia (recessive) probands observed in trans with a pathogenic variant without meeting FA phenotype. No such proband data is available for NM_024675.4:c.928A>G.	cspec
BS3	N/A	PALB2 VCEP states BS3 is not applicable.	cspec
BS4	Not met	PALB2 VCEP requires quantitative co-segregation analysis (LOD score or Bayes Factor) demonstrating lack of segregation. No such data is available for NM_024675.4:c.928A>G.	cspec
BP1	Met	PALB2 VCEP assigns BP1 (Supporting) to all missense variants in PALB2, given the very low likelihood that missense variants in this gene are pathogenic. NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant.	cspec
BP2	N/A	PALB2 VCEP states BP2 is not applicable.	cspec
BP4	N/A	PALB2 VCEP states for BP4: 'Missense: Do not use.' The splicing sub-rule (SpliceAI ≤0.1) also states 'Do not apply for missense variants.'	cspec spliceai
BP5	N/A	PALB2 VCEP states BP5 is not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and PALB2 has moderate penetrance.	cspec
BP6	N/A	PALB2 VCEP states BP6 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 is applicable only to synonymous and deep intronic variants per the PALB2 VCEP. NM_024675.4:c.928A>G is a missense variant (p.Ser310Gly).	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.