NM_024675.3:c.3049G>A

PALB2 · NP_078951.2:p.(Ala1017Thr) · NM_024675.3

GRCh37: chr16:23632747 C>T · GRCh38: chr16:23621426 C>T

Gene: PALB2 Transcript: NM_024675.3

Final call

VUS

BP1 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Ala1017Thr)

gnomAD AF

8.053993975612507e-06 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_024675.3:c.3049G>A (p.Ala1017Thr) is a missense variant in PALB2, a gene for which loss of function is an established mechanism of PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia complementation group N (autosomal recessive).

This variant has been classified as a Variant of Uncertain Significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (ClinVar Variation ID: 830187) and by seven clinical laboratories.

In gnomAD v4.1, this variant is present at an overall allele frequency of 0.000081% (13/1,614,106 alleles; grpmax FAF=0.0075%), with the highest frequency in the South Asian population (0.0132%; 12/91,078 alleles). The gnomAD v2.1 frequency is 0.00040% (1/251,448 alleles).

SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL score is 0.202 and BayesDel score is -0.306, both in ranges consistent with a benign computational prediction, though in silico predictors are not used for missense variants under the PALB2 VCEP framework.

Under the PALB2 VCEP v1.2.0 framework, BP1 (Supporting) is met because all PALB2 missense variants are assigned BP1 at Supporting strength, given the very low rate of functional missense variants in PALB2. No other criteria are met under this VCEP framework.

The PM2 (Supporting) criterion is not met because the variant's gnomAD v4.1 frequency (0.00081%) exceeds the VCEP threshold of ≤0.000333%. Population frequency criteria BA1 (>0.1%) and BS1 (>0.01%) are also not met, as the grpmax FAF (0.0075%) falls below both thresholds.

PS4 is not met; although this variant has been observed in 3 cancer cases in a case-control study (Momozawa et al. 2018), no formal odds ratio or statistical significance test meeting the VCEP threshold (OR≥3, p≤0.05) has been computed for this individual variant.

Many ACMG/AMP criteria are not applicable under the PALB2 VCEP for missense variants, including PVS1 (not a null variant), PS1/PP3/BP4 (missense excluded), PM1 (missense mechanism not confirmed), PM5 (truncation/splice only), PP2 (missense mechanism not confirmed), and PS3/BS3 (not used in this VCEP).

Several criteria (PP1, BS2, BS4) remain not assessed due to absence of published co-segregation, healthy adult proband, or non-segregation data for this specific variant.

With only BP1_Supporting met and no pathogenic criteria met, this variant does not satisfy the criteria for Likely Benign (requires ≥2 benign supporting or 1 strong benign + ≥1 supporting benign). The variant remains classified as a Variant of Uncertain Significance (VUS) under the PALB2 VCEP v1.2.0 framework.

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 is not applicable to missense variants. NM_024675.3:c.3049G>A is a missense substitution (p.Ala1017Thr) and does not fall into any null-variant bucket (nonsense, frameshift, canonical ±1,2 splice consensus) defined by the PALB2 VCEP PVS1 Decision Tree. The pvs1_variant_assessment confirms this variant does not qualify for generic PVS1.	pvs1_variant_assessment cspec
PS1	N/A	The PALB2 VCEP restricts PS1 to splicing changes (PALB2 PS1 Splicing table) and explicitly states 'Missense: Do not use.' This variant is a missense change with SpliceAI max delta score of 0.00, indicating no predicted splice impact. No pathogenic variant at the same amino acid with a different nucleotide change has been established.	cspec spliceai
PS2	N/A	The PALB2 VCEP declares PS2 not applicable: '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.' As breast cancer is relatively common, de novo is unlikely to inform autosomal dominant disease.	cspec
PS3	N/A	The PALB2 VCEP declares PS3 not applicable as a standalone criterion. Per VCEP instructions, functional evidence for PALB2 missense variants is not assessed under PS3; protein functional studies follow ATM-specific assay guidance and RNA studies use PVS1_O with curator-modulated strength.	cspec
PS4	Not met	The PALB2 VCEP PS4 requires formal case-control statistics (p-value ≤0.05 AND odds ratio/relative risk ≥3 OR lower 95% CI ≥1.5). This variant has been observed in 2 breast cancer and 1 prostate cancer cases in Momozawa et al. (2018) with absence from 11,279 controls, but no formal odds ratio or statistical test has been computed for this individual variant. Raw case counts are insufficient to meet the VCEP threshold. The VCEP also withholds PS4_Moderate for proband counting.	cspec gnomad_v4
PS5	N/A	PS5 is not enumerated in the PALB2 VCEP criteria, and its supporting counterpart PP5 is explicitly declared 'Not Applicable for this VCEP.' By extension, PS5 is not used in the PALB2 VCEP framework.	cspec
PM1	N/A	The PALB2 VCEP declares PM1 not applicable: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' No mutational hotspot or critical functional domain has been validated for PALB2 missense variants.	cspec
PM2	Not met	The PALB2 VCEP PM2_Supporting requires a frequency ≤1/300,000 (0.000333%) in gnomAD v4. In gnomAD v4.1, this variant has an overall allele frequency of 0.00081% (13/1,614,106 alleles), which exceeds the PM2 threshold. The variant is concentrated in the South Asian population (AF=0.0132%, 12/91,078). Per VCEP guidance, PM2 is not considered a conflicting piece of evidence for variants otherwise leaning benign.	gnomad_v4 cspec
PM5	N/A	The PALB2 VCEP PM5_Supporting applies only to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or splice variants with NMD-prone PTCs upstream of p.Tyr1183. The VCEP explicitly states: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' This variant is a missense change (p.Ala1017Thr).	cspec pm5_candidates
PM6	N/A	The PALB2 VCEP declares PM6 not applicable: '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.'	cspec
PP1	Not assessed	No published co-segregation analysis for NM_024675.3:c.3049G>A with PALB2-related cancer predisposition has been identified in the literature. The PALB2 VCEP requires, for autosomal dominant disease, LOD ≥0.3 or Bayes Factor (LR) ≥2:1 for Supporting-level evidence, or for autosomal recessive disease, segregation in ≥1 affected relative. Without family segregation data, PP1 cannot be evaluated.	cspec
PP2	N/A	The PALB2 VCEP declares PP2 not applicable: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' PP2 requires a gene where missense variants are a common mechanism of disease with a low rate of benign missense variation.	cspec
PP3	N/A	The PALB2 VCEP PP3 explicitly states: 'Missense: Do not use.' PP3 for PALB2 is restricted to splicing predictions (SpliceAI ≥0.2) for silent, missense/in-frame, and intronic variants. Although SpliceAI delta is 0.00 for this variant, the PP3 criterion is not applicable to missense variants per VCEP rules regardless of splicing predictions. In silico protein predictors (REVEL=0.202, BayesDel=-0.305671) are not used under this VCEP.	cspec spliceai revel bayesdel
PP4	N/A	The PALB2 VCEP declares PP4 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	The PALB2 VCEP declares PP5 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion should not be used in PALB2 variant interpretation.	cspec
BA1	Not met	The PALB2 VCEP BA1 (Stand Alone) requires a grpmax filtering allele frequency >0.1% in gnomAD v4. The grpmax FAF for this variant is 0.0075% (7.506e-05), which is well below the >0.1% threshold for BA1. The variant is too rare in population databases to meet this criterion.	gnomad_v4 cspec
BS1	Not met	The PALB2 VCEP BS1 (Strong) requires a grpmax filtering allele frequency >0.01% in gnomAD v4. The grpmax FAF for this variant is 0.0075% (7.506e-05), which falls below the >0.01% threshold. The variant is not sufficiently common in population databases to meet BS1.	gnomad_v4 cspec
BS2	Not assessed	The PALB2 VCEP BS2 is applicable for Fanconi anemia (recessive) but requires observation in healthy adult individuals who are not from population-based cohorts such as gnomAD. No published reports of NM_024675.3:c.3049G>A in confirmed healthy adults (outside gnomAD) have been identified. The variant is present in gnomAD (13 heterozygotes in v4.1) but these cannot be used for BS2 per VCEP rules.	cspec gnomad_v4
BS3	N/A	The PALB2 VCEP declares BS3 not applicable. Per VCEP instructions, functional studies showing no damaging effect are assessed under other criteria (BP7 for RNA studies).	cspec
BS4	Not assessed	No published analysis showing lack of segregation of NM_024675.3:c.3049G>A with disease in affected family members has been identified. The PALB2 VCEP BS4 requires quantitative co-segregation analysis (LOD ≤-1.28 for Strong, LOD ≤-0.32 for Supporting). Without family segregation data showing non-segregation, BS4 cannot be evaluated.	cspec
BP1	Met	The PALB2 VCEP BP1_Supporting applies to ALL PALB2 missense variants. Per the VCEP: '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 not yet confirmed or refuted but are thought to be exceedingly rare.' NM_024675.3:c.3049G>A is a missense variant (p.Ala1017Thr) and therefore qualifies for BP1 at Supporting strength.	cspec
BP2	N/A	The PALB2 VCEP declares BP2 not applicable. Observed in trans/cis phase data is assessed using the ATM PM3/BP2 table per VCEP instructions, but BP2 as a standalone criterion is not used for PALB2.	cspec
BP4	N/A	The PALB2 VCEP BP4 explicitly states: 'Missense: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants.' Although SpliceAI delta is 0.00 (≤0.1) and computational scores are in the benign range (REVEL=0.202, BayesDel=-0.306), BP4 is not applied to missense variants in this VCEP framework.	cspec spliceai revel bayesdel
BP5	N/A	The PALB2 VCEP declares BP5 not applicable: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). 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	The PALB2 VCEP declares BP6 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use in PALB2 variant interpretation.	cspec
BP7	N/A	The PALB2 VCEP BP7 Supporting applies to synonymous and deep intronic variants (further than +7 at donor and -21 at acceptor sites). NM_024675.3:c.3049G>A is a missense variant, not a synonymous or deep intronic change. BP7(RNA) applies only to silent substitutions with demonstrated lack of aberrant RNA defect, which does not apply to this missense variant.	cspec

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