NM_024675.3:c.82T>A

PALB2 · NP_078951.2:p.(Tyr28Asn) · NM_024675.3

GRCh37: chr16:23649417 A>T · GRCh38: chr16:23638096 A>T

Gene: PALB2 Transcript: NM_024675.3

Final call

VUS

PM2 supporting BP1 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Tyr28Asn)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 applies only to null variants (nonsense, frameshift, canonical splice) or variants with a demonstrated splice defect per the PALB2 VCEP PVS1 Decision Tree. NM_024675.3:c.82T>A is a missense variant (p.Tyr28Asn) with no predicted splice impact (SpliceAI max delta score = 0.00), and therefore does not meet PVS1 eligibility criteria.	cspec spliceai
PS1	N/A	Per PALB2 VCEP v1.2.0, PS1 is not used for missense variants: 'Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PS1 is only applied to splicing variants via the PALB2 PS1 Splicing table. NM_024675.3:c.82T>A is a missense variant with no splice impact (SpliceAI delta = 0.00).	cspec
PS2	N/A	PS2 is marked not applicable by the PALB2 VCEP v1.2.0: informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related disease, and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	N/A	PS3 is marked not applicable by the PALB2 VCEP v1.2.0 for protein-level functional studies. The VCEP directs use of PVS1_O (RNA) for RNA-level splice defects only.	cspec
PS4	Not met	PS4 requires case-control studies demonstrating significantly increased prevalence in affected individuals versus controls (p ≤ 0.05 AND OR ≥ 3 or lower 95% CI ≥ 1.5). No case-control study reporting NM_024675.3:c.82T>A in affected versus unaffected individuals was identified. The variant is absent from gnomAD population databases and classified as Uncertain Significance by the ClinGen Expert Panel (ClinVar ID 410148), indicating insufficient case-level evidence to meet PS4 thresholds.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a criterion in the PALB2 VCEP v1.2.0 framework and is not part of the standard ACMG/AMP 2015 criteria set used as a fallback. This criterion does not exist in the applicable classification framework.	cspec
PM1	N/A	Per PALB2 VCEP v1.2.0, PM1 is not applicable: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' Additionally, the variant does not lie in a statistically significant hotspot.	cspec
PM2	Met	Per PALB2 VCEP v1.2.0, PM2 is applied at supporting strength when the variant frequency is ≤ 1/300,000 (0.000333%) in gnomAD v4. NM_024675.3:c.82T>A is absent from both gnomAD v2.1 and gnomAD v4.1, meeting the PM2_Supporting threshold.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	Per PALB2 VCEP v1.2.0, PM5 is not used for missense changes: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5 is restricted to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or splice variants with confirmed NMD-prone splicing impact.	cspec
PM6	N/A	PM6 is marked not applicable by the PALB2 VCEP v1.2.0: informative de novo occurrences have not yet been observed for autosomal dominant or autosomal recessive PALB2-related disease.	cspec
PP1	Not met	PP1 requires co-segregation of the variant with disease in multiple affected family members (AD: LOD ≥ 0.3 or LR ≥ 2:1 for supporting; AR: segregation in ≥ 1 affected relative). No published co-segregation data for NM_024675.3:c.82T>A were identified. Exploratory literature searches returned no family studies with this variant.	cspec
PP2	N/A	Per PALB2 VCEP v1.2.0, PP2 is not applicable: 'Do not use: Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.'	cspec
PP3	N/A	Per PALB2 VCEP v1.2.0, PP3 is not used for missense variants. Published in silico predictors have not achieved reliable functional outcome prediction for PALB2 missense variants. PP3 is only applied for splicing predictions when SpliceAI ≥ 0.2; NM_024675.3:c.82T>A has a SpliceAI max delta score of 0.00, which does not meet this threshold.	cspec spliceai
PP4	N/A	Per PALB2 VCEP v1.2.0, PP4 is not applicable: breast cancer is a disease with multiple genetic etiologies (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For the AR condition (Fanconi anemia), PM3 is used instead for specific phenotype considerations.	cspec
PP5	N/A	Per PALB2 VCEP v1.2.0, PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	BA1 requires a Grpmax Filtering AF > 0.1% in gnomAD v4. NM_024675.3:c.82T>A is absent from gnomAD v4.1 (0 alleles observed), far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	BS1 requires a Grpmax Filtering AF > 0.01% in gnomAD v4. NM_024675.3:c.82T>A is absent from gnomAD v4.1, which does not meet this threshold.	gnomad_v4 cspec
BS2	Not met	BS2 (Fanconi Anemia BS2 tables) requires observation of the variant in a healthy adult individual for a recessive disorder expected to be fully penetrant at an early age, with points assigned per proband. No published report of NM_024675.3:c.82T>A in a healthy adult in a Fanconi anemia context was identified.	cspec
BS3	N/A	BS3 is marked not applicable by the PALB2 VCEP v1.2.0. For protein-level functional studies showing no damaging effect, the VCEP directs use of alternative criteria. For RNA-level evidence of no splice defect, BP7(RNA) is used instead.	cspec
BS4	Not met	BS4 requires quantitative co-segregation analysis demonstrating lack of segregation (LOD ≤ -0.32 for supporting, ≤ -0.64 for moderate, ≤ -1.28 for strong). No segregation or non-segregation data for NM_024675.3:c.82T>A were identified in the literature or databases.	cspec
BP1	Met	Per PALB2 VCEP v1.2.0, BP1 applies to all missense variants in PALB2 at supporting benign strength. PALB2 has a low rate of missense variants that are non-functional in relevant assays, and true missense pathogenic variants are thought to be exceedingly rare. NM_024675.3:c.82T>A (p.Tyr28Asn) is a missense variant and qualifies for BP1.	cspec
BP2	N/A	Per PALB2 VCEP v1.2.0, BP2 is not applicable. The VCEP directs use of the ATM PM3/BP2 table, but this framework element is not applied to novel missense variants without co-occurrence data.	cspec
BP4	N/A	Per PALB2 VCEP v1.2.0, BP4 is not used for missense variants: published in silico predictors have not achieved reliable functional outcome prediction for PALB2 missense variants. BP4 is only applied for splicing predictions when SpliceAI ≤ 0.1; while NM_024675.3:c.82T>A has SpliceAI delta = 0.00, the VCEP explicitly states 'Missense: Do not use.'	cspec spliceai
BP5	N/A	Per PALB2 VCEP v1.2.0, BP5 is not applicable. The VCEP states: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype. In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.'	cspec
BP6	N/A	Per PALB2 VCEP v1.2.0, BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous variants and deep intronic variants per PALB2 VCEP v1.2.0. NM_024675.3:c.82T>A is a missense variant (p.Tyr28Asn), not a synonymous or deep intronic variant. BP7(RNA) requires observed lack of aberrant RNA defect, but no RNA studies for this variant have been identified.	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.