LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-25
Case ID: NM_024675.4_c.1652A_G_20260625_152516
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.4:c.1652A>G

PALB2  · NP_078951.2:p.(Tyr551Cys)  · NM_024675.4
GRCh37: chr16:23646215 T>C  ·  GRCh38: chr16:23634894 T>C
Gene: PALB2 Transcript: NM_024675.4
Final call
PM2 supporting 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.(Tyr551Cys)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_024675.4:c.1652A>G (p.Tyr551Cys) is a missense variant in PALB2, a gene where loss of function is an established disease mechanism for PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia complementation group N (autosomal recessive).
2
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 across all populations, meeting the CSPEC PM2_Supporting threshold of ≤ 0.000333% allele frequency (PM2_Supporting).
3
CSPEC PALB2 v1.2.0 applies BP1 (Supporting) to all missense variants, based on evidence that PALB2 has a very low rate of functional missense variants and true pathogenic missense changes are thought to be exceedingly rare (BP1_Supporting).
4
Multiple CSPEC criteria are explicitly not applicable to PALB2 missense variants: PS1, PM1, PM5, PP2, PP3, and BP4 are all prohibited by VCEP rules because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2.
5
PS3 and BS3 (functional studies) are marked not applicable by CSPEC; PS2 and PM6 (de novo) are not applicable; PP4 (phenotype specificity) and PP5 (reputable source) are not applicable for this VCEP; BP2, BP5, BP6, and BP7 are not applicable for this variant type.
6
PS4 (case-control), PP1 (co-segregation), BS2 (FA probands), and BS4 (lack of segregation) could not be assessed due to absence of clinical proband, segregation, or case-control data in the evidence set.
7
The variant has been reported in ClinVar as Uncertain Significance (VCV000856757) by 3 clinical laboratories with review status 'criteria provided, single submitter.' No expert panel classification is available.
8
No variant-specific functional or clinical evidence was identified in the literature. All PMIDs associated with this ClinVar entry are general guidelines or review articles (ACMG/AMP standards, genetic counseling recommendations, USPSTF statements) that do not mention NM_024675.4:c.1652A>G or p.Tyr551Cys.
9
Criterion summary: one pathogenic supporting criterion met (PM2_Supporting) and one benign supporting criterion met (BP1_Supporting). Per ACMG/AMP 2015 combining rules adopted by the CSPEC PALB2 framework (Rule31), the presence of both benign supporting and pathogenic supporting evidence results in a classification of Uncertain Significance with conflicting evidence.
Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.
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 Variant is a missense substitution (p.Tyr551Cys), not a null variant. The PALB2 PVS1 Decision Tree applies to nonsense, frameshift, and canonical splice site variants. SpliceAI max delta score of 0.03 confirms no cryptic splice impact that would trigger PVS1 consideration.
pvs1_variant_assessment spliceai
PS1 N/A CSPEC PALB2 v1.2.0 explicitly states: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PS1 Splicing table applies only to splicing variants, not missense substitutions without splice impact.
cspec
PS2 N/A CSPEC PALB2 v1.2.0 marks PS2 as not applicable: de novo occurrences have not yet been observed for PALB2 autosomal dominant disease.
cspec
PS3 N/A CSPEC PALB2 v1.2.0 marks PS3 as not applicable for this VCEP. Functional protein assays are not validated for PALB2 missense variant assessment.
cspec
PS4 Not assessed CSPEC PS4 requires case-control studies with p ≤ 0.05 AND (OR/HR/RR ≥ 3 OR lower 95% CI ≥ 1.5). No case-control study data is available for this variant. PS4_Moderate (proband counting) is explicitly not used per CSPEC.
cspec clinvar
PS5 N/A PS5 is not a recognized criterion in the ACMG/AMP 2015 framework (PMID:25741868) or the PALB2 VCEP specifications.
PM1 N/A CSPEC PALB2 v1.2.0 states: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' PM1 (mutational hotspot / critical domain) is not applicable for PALB2 missense variants.
cspec
PM2 Met Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. This meets the CSPEC PM2_Supporting threshold of frequency ≤ 0.000333% (≤ 1/300,000) in gnomAD v4. Per CSPEC, PM2 is used at Supporting strength, not Moderate.
gnomad_v2 gnomad_v4 gnomad_canada
PM5 N/A CSPEC PALB2 v1.2.0 states: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5_Supporting rule applies only to truncating variants upstream of p.Tyr1183 or splice variants. This is a missense substitution.
cspec pm5_candidates
PM6 N/A CSPEC PALB2 v1.2.0 marks PM6 as not applicable: informative de novo occurrences have not yet been observed for PALB2 AD or AR disease.
cspec
PP1 Not assessed CSPEC PP1 requires quantitative co-segregation analysis (LOD scores or Bayes Factor LR) for AD disease or segregation in affected relatives for AR disease. No segregation data is available for this variant.
cspec
PP2 N/A CSPEC PALB2 v1.2.0 states: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' PP2 is reserved for genes where missense variants are a common disease mechanism, which is not established for PALB2.
cspec
PP3 N/A CSPEC PALB2 v1.2.0 states: 'Missense: Do not use.' In silico predictors have not been validated for PALB2 missense variant functional outcome. SpliceAI max delta 0.03 is well below the 0.2 threshold, REVEL 0.007 and BayesDel -0.668 both predict benign, but PP3 is not applied to missense variants per VCEP rules.
cspec revel bayesdel spliceai
PP4 N/A CSPEC PALB2 v1.2.0 states PP4 is not applicable: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.'
cspec
PP5 N/A CSPEC PALB2 v1.2.0 states: 'Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
cspec
BA1 Not met CSPEC BA1 requires Grpmax Filtering AF > 0.1% in gnomAD v4. The variant is absent from gnomAD v4.1 (0 alleles across all populations). BA1 threshold is not met.
gnomad_v4
BS1 Not met CSPEC BS1 requires Grpmax Filtering AF > 0.01% in gnomAD v4. The variant is absent from gnomAD v4.1 across all populations. BS1 threshold is not met.
gnomad_v4
BS2 Not assessed CSPEC BS2 requires Fanconi Anemia BS2 proband point-counting tables (BS2_Strong ≥ 4 points, BS2_Moderate = 2 points, BS2_Supporting = 1 point). No Fanconi Anemia proband data available for this variant. Cannot be assessed without clinical proband information.
cspec
BS3 N/A CSPEC PALB2 v1.2.0 marks BS3 as not applicable for this VCEP. Functional benign assays are not validated for PALB2 missense variants.
cspec
BS4 Not assessed CSPEC BS4 requires quantitative co-segregation analysis (LOD ≤ -1.28 or LR ≤ 0.053 for Strong; LOD ≤ -0.64 or LR ≤ 0.23 for Moderate; LOD ≤ -0.32 or LR ≤ 0.48 for Supporting). No co-segregation data available for this variant.
cspec
BP1 Met CSPEC PALB2 v1.2.0 explicitly states: 'Apply to all missense variants.' Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are thought to be exceedingly rare. This rule applies to all missense variants, including p.Tyr551Cys.
cspec
BP2 N/A CSPEC PALB2 v1.2.0 marks BP2 as not applicable. Observed in trans/cis with a pathogenic variant is assessed via the ATM PM3/BP2 table, not independently for PALB2.
cspec
BP3 N/A Variant is a single-nucleotide missense substitution, not an in-frame deletion/insertion. CSPEC also marks BP3 as not applicable for PALB2.
cspec
BP4 N/A CSPEC PALB2 v1.2.0 states: 'Missense: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants.' Although SpliceAI max delta 0.03 indicates no predicted splice impact and both REVEL (0.007) and BayesDel (-0.668) predict benign, BP4 is not applied to missense variants per VCEP rules.
cspec spliceai revel bayesdel
BP5 N/A CSPEC PALB2 v1.2.0 marks BP5 as not applicable: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype.'
cspec
BP6 N/A CSPEC PALB2 v1.2.0 states: 'Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
cspec
BP7 N/A CSPEC BP7 applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). This variant is a missense substitution (c.1652A>G, p.Tyr551Cys), not a synonymous or intronic variant.
cspec
PM3 N/A Skipped per user instruction. CSPEC PM3 requires Fanconi Anemia proband point-counting tables — no FA trans configuration data available in evidence set.
PM4 N/A CSPEC PALB2 v1.2.0 limits PM4 to stop-loss variants only. This variant is a single-nucleotide missense substitution, not a stop-loss variant.
cspec
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