NM_024675.4:c.740C>G

PALB2 · NP_078951.2:p.(Thr247Arg) · NM_024675.4

GRCh37: chr16:23647127 G>C · GRCh38: chr16:23635806 G>C

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Thr247Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_024675.4:c.740C>G (p.Thr247Arg) is a missense variant in exon 4 of PALB2 identified in 1 of 1996 Australian familial breast cancer cases and 0 of 1998 cancer-free controls (Thompson et al. 2015).

Under the ClinGen PALB2 VCEP v1.2.0 framework, most pathogenic criteria are not applicable to missense variants: PVS1 (null variant only), PS1 (missense excluded), PM1 (missense excluded), PM5 (truncating only), PP2 (missense excluded), PP3/BP4 (missense excluded). PS3/BS3 are not applicable per VCEP.

BP1_Supporting is met: the PALB2 VCEP applies BP1 to all missense variants at Supporting level, reflecting the very low likelihood that missense variants in PALB2 are pathogenic based on published functional data.

PM2 could not be assessed: gnomAD v4 frequency data is unavailable (scrape timed out). The variant has an rsID (rs587782658) and is present in population databases, but the exact allele frequency needed for the VCEP PM2_Supporting threshold (≤0.000333%) requires manual confirmation.

PS4 is not met: the single case observation (1/1996 cases vs 0/1998 controls) does not constitute a statistically significant case-control enrichment (p=0.48, Fisher's exact test).

No functional data (PS3 not applicable per VCEP), no segregation data (PP1/BS4 not assessed), no de novo reports (PS2/PM6 not applicable), and no Fanconi Anemia observations (BS2 not assessed) are available for this variant.

In silico predictors are mixed: REVEL score 0.065 and BayesDel -0.512 are benign-leaning; SpliceAI delta 0.00 predicts no splice impact. However, under VCEP rules, PP3 and BP4 are not applicable for missense variants regardless of predictor scores.

ClinVar classification is Uncertain significance (7 clinical laboratories) / Likely benign (1 laboratory), with no expert panel review. This is consistent with the limited evidence available for this missense variant.

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	NM_024675.4:c.740C>G is a missense variant (p.Thr247Arg). PVS1 applies only to null variants (nonsense, frameshift, canonical splice sites). This variant does not fall into any PVS1-eligible null-variant bucket.	pvs1_variant_assessment cspec
PS1	N/A	PALB2 VCEP v1.2.0 specifies: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PS1 is restricted to splicing variants via the PALB2 PS1 Splicing table; missense variants are explicitly excluded.	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 and de novo AR conditions are unlikely to be informed by phase.' PS2 is not applicable for PALB2 under this VCEP.	cspec
PS3	N/A	PALB2 VCEP v1.2.0 declares PS3 not applicable for protein-level functional studies in PALB2. No variant-specific functional data identified in the literature; OncoKB records this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence.	cspec oncokb
PS4	Not met	The variant was observed in 1 of 1996 familial breast cancer cases and 0 of 1998 controls in Thompson et al. 2015 (PMID:26283626) — a single observation insufficient to meet VCEP PS4 requirements (case-control study with p≤0.05 AND OR≥3 OR lower 95% CI≥1.5). No other case-control enrichment data identified.	PMID:26283626
PS5	Not met	No reputable source (e.g., expert panel, clinical guideline) has reported this variant as pathogenic. ClinVar classification is Uncertain significance (7 labs) / Likely benign (1 lab); no expert panel classification exists.	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.' PM1 is explicitly excluded for missense variants in PALB2 under this VCEP.	cspec
PM2	Not assessed	PALB2 VCEP PM2_Supporting requires frequency ≤0.000333% in gnomAD v4. The gnomAD v4 scrape for this variant timed out (120s) during evidence gathering. The variant has an rsID (rs587782658) and Invitae's ClinVar submission notes it is present in population databases, but the exact gnomAD v4 allele frequency could not be confirmed. Manual lookup required.
PM5	N/A	PALB2 VCEP v1.2.0 PM5 applies only to frameshifting/truncating variants with premature termination codons upstream of p.Tyr1183, and to splice variants where PVS1 is applied. Missense variants are explicitly excluded: 'Do not use for missense changes.' PM5 candidates artifact confirms this is a truncation-cutoff rule.	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.' PM6 is not applicable for PALB2 under this VCEP.	cspec
PP1	Not assessed	No co-segregation data or family studies evaluating NM_024675.4:c.740C>G were identified in the literature or evidence packet. Thompson et al. 2015 reported a single carrier among 1996 cases; no family segregation analysis was performed.
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.' PP2 is not applicable for PALB2 missense variants.	cspec
PP3	N/A	PALB2 VCEP v1.2.0: 'Missense: Do not use.' PP3 is restricted to splicing variants with SpliceAI ≥0.2. SpliceAI max delta score is 0.00 for this variant, confirming no predicted splice impact. REVEL (0.065) and BayesDel (-0.512) scores are both in the benign range, but in silico missense predictors are explicitly excluded from PP3 under this VCEP.	cspec spliceai revel bayesdel
PP4	N/A	PALB2 VCEP v1.2.0: '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.' PP4 is not applicable for PALB2.	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.' PP5 is not applicable for this VCEP.	cspec
BA1	Not met	PALB2 VCEP BA1 requires Grpmax Filtering AF >0.1% in gnomAD v4. While gnomAD v4 data timed out, the variant was absent from gnomAD-Canada (0 carriers) and was found in only 1 of 3994 individuals (0.025%) in the Thompson et al. 2015 case-control cohort. Available evidence is inconsistent with a population frequency >0.1%.	gnomad_canada PMID:26283626
BS1	Not assessed	PALB2 VCEP BS1 requires Grpmax Filtering AF >0.01% in gnomAD v4. gnomAD v4 scrape timed out. The variant has an rsID (rs587782658) and is present in population databases per ClinVar/Invitae, but exact frequency is unknown. Manual lookup needed.
BS2	Not assessed	PALB2 VCEP BS2 requires Fanconi Anemia proband scoring. No Fanconi Anemia cases with this variant were identified in the evidence packet. BS2 requires curated phenotype data not available in this data pull.
BS3	N/A	PALB2 VCEP v1.2.0: Not applicable. The VCEP redirects protein-level functional analyses to PVS1/BP7 modulation and does not use BS3.	cspec
BS4	Not assessed	No co-segregation or family study data available for this variant. BS4 requires quantitative segregation analysis (LOD scores). The single carrier identified in Thompson et al. 2015 had no accompanying family segregation data.
BP1	Met	PALB2 VCEP v1.2.0: 'Apply to all missense variants' at Supporting strength. 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 missense variant (p.Thr247Arg) is eligible for BP1_Supporting.	cspec
BP2	N/A	PALB2 VCEP v1.2.0: 'Use ATM PM3/BP2 table.' BP2 is not applicable under the PALB2 VCEP — the VCEP redirects to the ATM-specific BP2 framework.	cspec
BP3	N/A	Skipped per instructions: trivially not_applicable for substitution variant.
BP4	N/A	PALB2 VCEP v1.2.0: 'Missense: Do not use.' BP4 is restricted to splicing variants with SpliceAI ≤0.1; missense variants are explicitly excluded. SpliceAI max delta is 0.00, confirming no predicted splice impact, but BP4 cannot be applied to missense under this VCEP.	cspec spliceai
BP5	N/A	PALB2 VCEP v1.2.0: Not applicable. VCEP rationale: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; PALB2 has moderate penetrance and will naturally occur with other pathogenic variants.	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.' BP6 is not applicable for this VCEP.	cspec
BP7	Not met	PALB2 VCEP BP7 applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). This is a missense variant (c.740C>G, p.Thr247Arg), not synonymous. No RNA-level data available to assess BP7_RNA for aberrant splicing. SpliceAI predicts no splice impact (delta=0.00) but this does not qualify for BP7 which is for silent/intronic variants.	cspec spliceai

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.