NM_024675.4:c.509_510delGA

PALB2 · NP_078951.2:p.(Arg170IlefsTer14) · NM_024675.4

GRCh37: chr16:23647356 ATC>A · GRCh38: chr16:23636035 ATC>A

Gene: PALB2 Transcript: NM_024675.4

Final call

Pathogenic

PVS1 strong PS4 strong PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Arg170IlefsTer14)

gnomAD AF

1.8587291497057632e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_024675.4:c.509_510delGA (p.Arg170IlefsTer14) is a frameshift deletion in exon 4 of PALB2 that introduces a premature termination codon at position 184, predicted to undergo nonsense-mediated decay and resulting in loss of all C-terminal functional domains including the WD40 repeat/BRCA2-binding region. Loss of function is an established disease mechanism for PALB2 (PVS1_Strong).

The variant is significantly enriched in breast cancer cases compared to population controls. Noskowicz et al. (2014) identified the variant in 10/3,924 (0.25%) unselected breast cancer patients from Central/Eastern Europe versus 0/2,827 healthy controls (p=0.007). Additional studies corroborate this enrichment: Dansonka-Mieszkowska et al. (2010) found the variant in 6/987 (0.6%) cancer cases versus 1/1,310 controls; Kluska et al. (2017) detected it in 0.5% of 807 BRCA1/2-negative breast/ovarian cancer patients; and Bogdanova et al. (2011) identified it in 2/203 bilateral breast cancer patients. Collectively, these studies meet PS4 at Strong strength.

The premature termination codon at position 184 lies upstream of p.Tyr1183, the most C-terminal known pathogenic variant in PALB2, consistent with loss of critical functional domains. Under the PALB2 VCEP, this satisfies PM5_Supporting.

The variant is present at low frequency in gnomAD (v4.1: 30/1,614,006, 0.00186%; v2.1: 9/251,446, 0.00358%), with no homozygotes. This frequency exceeds the PALB2 VCEP PM2_Supporting threshold (≤0.000333%) and remains well below benign population thresholds (BA1 >0.1%, BS1 >0.01%), providing neither pathogenic nor benign population evidence.

SpliceAI predicts no cryptic splice effect (max delta = 0.00). No co-segregation or non-segregation data are available. No functional studies specific to this variant have been published.

Final determination: Rule5 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 Pathogenic.

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	Met	NM_024675.4:c.509_510delGA is a frameshift deletion in exon 4 of 13 that introduces a premature termination codon at position 184 (p.Arg170IlefsTer14), upstream of the final exon and predicted to undergo nonsense-mediated decay. Loss of function is an established disease mechanism for PALB2. Under the PALB2 VCEP PVS1 decision tree, frameshift variants in exon 4 are eligible for PVS1; strength assigned as Strong given the variant is NMD-competent, though exon 4 alternative splicing considerations may warrant downgrade per VCEP guidance.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 in the PALB2 VCEP applies only to splicing variants via the PALB2 PS1 Splicing table (PMID: 37352859). This is a frameshift variant, not a splice site change. Classic PS1 (same amino acid change as known pathogenic) also does not apply to frameshift variants.
PS2	N/A	The PALB2 VCEP designates PS2 as Not Applicable. De novo occurrences have not been observed for PALB2-associated autosomal dominant disease.
PS3	N/A	The PALB2 VCEP designates PS3 as Not Applicable.
PS4	Met	A case-control study by Noskowicz et al. (2014) found NM_024675.4:c.509_510delGA in 10 of 3,924 unselected breast cancer patients (0.25%) versus 0 of 2,827 healthy controls from Central and Eastern Europe (p=0.007), meeting the PALB2 VCEP PS4 threshold (p≤0.05 with OR≥3 or lower 95% CI≥1.5). Additional studies corroborate enrichment: Dansonka-Mieszkowska et al. (2010) found the variant in 6/987 cancer cases vs 1/1,310 controls; Kluska et al. (2017) found it in 0.5% of 807 cases; and Hilz et al. (2019) reported 0.35% in 2,480 cases vs 0% in 1,240 controls (RR=7.18).	PMID:28279176
PS5	N/A	PS5 is not addressed by the PALB2 VCEP specification and does not apply to frameshift variants (PS5 requires comparison of alternative nucleotide changes at the same residue, applicable to missense variants).
PM1	N/A	The PALB2 VCEP designates PM1 as Not Applicable because missense pathogenic variation in PALB2 has not been confirmed as a disease mechanism.
PM2	Not met	Under the PALB2 VCEP, PM2_Supporting requires a gnomAD v4 frequency ≤0.000333% (≤1/300,000). This variant has a gnomAD v4.1 allele frequency of 0.00186% (30/1,614,006 alleles), which exceeds the VCEP threshold. In gnomAD v2.1, it is present at 0.00358% (9/251,446 alleles). The variant does not meet the VCEP PM2 frequency cutoff.	gnomad_v2 gnomad_v4
PM4	N/A	The PALB2 VCEP designates PM4 as Not Applicable for in-frame insertions or deletions less than a single exon; PM4 is reserved for stop-loss variants only.
PM5	Met	Under the PALB2 VCEP, PM5_Supporting is applied to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183. This variant introduces a PTC at codon 184, well upstream of p.Tyr1183, consistent with loss of the WD40/BRCA2-binding domain and other C-terminal functional regions.
PM6	N/A	The PALB2 VCEP designates PM6 as Not Applicable. Informative de novo occurrences have not been observed for PALB2-associated autosomal dominant disease.
PP1	Not met	No co-segregation data are available for NM_024675.4:c.509_510delGA in published literature. The PALB2 VCEP requires quantitative co-segregation analysis (LOD ≥0.3 or LR ≥2:1 for Supporting, LOD ≥0.6 or LR ≥4:1 for Moderate, LOD ≥1.26 or LR ≥18:1 for Strong) for autosomal dominant conditions.
PP2	N/A	The PALB2 VCEP designates PP2 as Not Applicable because missense variation is not yet confirmed or refuted as a disease mechanism for PALB2.
PP3	Not met	Under the PALB2 VCEP, PP3 is applicable only for splicing variants with SpliceAI delta score ≥0.2. SpliceAI predicts no splice impact for this variant (max delta score = 0.00), and PP3 for missense variants is not used in the PALB2 VCEP.	spliceai
PP4	N/A	The PALB2 VCEP designates PP4 as Not Applicable because breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes.
PP5	N/A	The PALB2 VCEP designates PP5 as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1	Not met	The PALB2 VCEP BA1 threshold requires grpmax filtering AF >0.1% in gnomAD v4. This variant has a gnomAD v4.1 grpmax filtering AF of 0.00172% (1.724e-05), well below the BA1 threshold. The variant is too rare in population databases to meet BA1.	gnomad_v4
BS1	Not met	The PALB2 VCEP BS1 threshold requires grpmax filtering AF >0.01% in gnomAD v4. This variant has a gnomAD v4.1 grpmax filtering AF of 0.00172%, well below the BS1 threshold.	gnomad_v4
BS2	Not met	The PALB2 VCEP BS2 requires homozygous or compound heterozygous observations in healthy adult individuals per Fanconi Anemia BS2 tables. No such observations have been reported for NM_024675.4:c.509_510delGA. The variant is not observed in a homozygous state in gnomAD, and no healthy adults with biallelic PALB2 variants including this allele have been described.	gnomad_v2 gnomad_v4
BS3	N/A	The PALB2 VCEP designates BS3 as Not Applicable.
BS4	Not met	No non-segregation data are available for this variant. The PALB2 VCEP requires quantitative co-segregation analysis showing LOD ≤-1.28 (Strong), ≤-0.64 (Moderate), or ≤-0.32 (Supporting) to meet BS4. No studies have reported lack of segregation of NM_024675.4:c.509_510delGA with disease in affected families.
BP1	N/A	The PALB2 VCEP applies BP1 only to missense variants. NM_024675.4:c.509_510delGA is a frameshift variant.
BP2	N/A	The PALB2 VCEP designates BP2 as Not Applicable.
BP3	N/A	The PALB2 VCEP designates BP3 as Not Applicable because small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity for PALB2, and PALB2 does not have repetitive regions without known function.
BP4	N/A	The PALB2 VCEP BP4 applies to splicing predictions (SpliceAI ≤0.1) and is explicitly not applicable to missense variants. While SpliceAI predicts no splice impact (max delta = 0.00), this frameshift variant's disease mechanism is through protein truncation and NMD, not splicing. Applying BP4 to a frameshift variant is not clinically meaningful under this VCEP.	spliceai
BP5	N/A	The PALB2 VCEP designates BP5 as Not Applicable because cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and PALB2 has moderate penetrance with higher tolerance in the general population.
BP6	N/A	The PALB2 VCEP designates BP6 as Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7	N/A	BP7 in the PALB2 VCEP applies to synonymous and deep intronic variants. NM_024675.4:c.509_510delGA is a frameshift variant.

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