NM_024675.4:c.886dupA

PALB2 · NP_078951.2:p.(Met296AsnfsTer7) · NM_024675.4

GRCh37: chr16:23646980 A>AT · GRCh38: chr16:23635659 A>AT

Gene: PALB2 Transcript: NM_024675.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Met296AsnfsTer7)

gnomAD AF

3.0981237762411082e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_024675.4:c.886dupA (p.Met296AsnfsTer7) is a frameshift duplication in exon 4 of PALB2 that introduces a premature termination codon predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen PALB2 VCEP v1.2.0.

The variant is present in gnomAD v4.1 at an overall frequency of 0.00031% (5/1,613,880 alleles, no homozygotes), below the PALB2 VCEP PM2_Supporting threshold of 0.000333%, satisfying PM2 at supporting strength.

The premature termination codon at residue 302 lies upstream of p.Tyr1183, the most C-terminal known pathogenic variant in PALB2, satisfying PM5_Supporting under the PALB2 VCEP.

Under the ACMG/AMP 2015 combining rules adopted by the PALB2 VCEP, one Very Strong (PVS1) plus two Supporting (PM2, PM5) criteria satisfies Rule 4, yielding a classification of Pathogenic.

Final determination: Rule4 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	This frameshift duplication in exon 4 introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), far upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), and is predicted to trigger nonsense-mediated decay. PALB2 loss of function is an established disease mechanism under the ClinGen PALB2 VCEP (v1.2.0).	pvs1_gene_context pvs1_variant_assessment gnomad_v4 cspec
PS1	N/A	PS1 under the PALB2 VCEP (v1.2.0) is applicable only to splicing variants with reference to the PALB2 PS1 Splicing table; this is a frameshift duplication.	cspec
PS2	N/A	PS2 is designated Not Applicable by the PALB2 VCEP (v1.2.0): informative de novo occurrences have not been observed for autosomal dominant PALB2-related disease.	cspec
PS3	N/A	PS3 is designated Not Applicable by the PALB2 VCEP (v1.2.0); functional studies for protein-level effects are not part of the current PALB2 variant interpretation framework.	cspec
PS4	Not met	No case-control study has been identified that evaluates NM_024675.4:c.886dupA specifically with an odds ratio ≥3 or lower 95% CI ≥1.5 and p≤0.05, as required by the PALB2 VCEP PS4 rule.	cspec
PS5	N/A	PS5 is not defined in the PALB2 VCEP framework (v1.2.0); the ClinGen SVI VCEP Review Committee designates the closely related PP5 as Not Applicable for this VCEP.	cspec
PM1	N/A	PM1 is designated Not Applicable by the PALB2 VCEP (v1.2.0): missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.	cspec
PM2	Met	This variant has an overall allele frequency of 0.00031% (5/1,613,880 alleles) in gnomAD v4.1, which is below the PALB2 VCEP PM2_Supporting threshold of ≤0.000333% (1/300,000). No homozygotes have been observed.	gnomad_v4 cspec
PM4	N/A	PM4 under the PALB2 VCEP (v1.2.0) is restricted to stop-loss variants only; this is a frameshift duplication.	cspec
PM5	Met	This frameshift variant introduces a premature termination codon at position 302 (p.Met296AsnfsTer7), upstream of the most C-terminal known PALB2 pathogenic variant (p.Tyr1183), satisfying the PALB2 VCEP PM5_Supporting rule for truncating variants.	pm5_candidates cspec
PM6	N/A	PM6 is designated Not Applicable by the PALB2 VCEP (v1.2.0): informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	No co-segregation data (LOD scores, Bayes factors, or affected relative counts) are available for NM_024675.4:c.886dupA.	cspec
PP2	N/A	PP2 is designated Not Applicable by the PALB2 VCEP (v1.2.0): missense is not yet confirmed or refuted as a mechanism of disease for PALB2.	cspec
PP3	N/A	PP3 under the PALB2 VCEP (v1.2.0) is applicable only to splicing variants with SpliceAI ≥0.2. This frameshift variant has a SpliceAI max delta score of 0.01, and PP3 is excluded for missense variants; it does not apply to frameshift variants.	spliceai cspec
PP4	N/A	PP4 is designated Not Applicable by the PALB2 VCEP (v1.2.0): breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes.	cspec
PP5	N/A	PP5 is designated Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The grpmax filtering allele frequency for this variant is 0.00175% (grpmax FAF = 1.747e-05) in gnomAD v4.1, well below the BA1 threshold of >0.1%.	gnomad_v4 cspec
BS1	Not met	The grpmax filtering allele frequency for this variant is 0.00175% (grpmax FAF = 1.747e-05) in gnomAD v4.1, below the BS1 threshold of >0.01%.	gnomad_v4 cspec
BS2	Not met	No individuals homozygous or compound heterozygous for this variant have been reported with a Fanconi anemia phenotype, and no BS2 proband-level data are available for point assignment under the PALB2 VCEP Fanconi Anemia BS2 tables.	gnomad_v4 cspec
BS3	N/A	BS3 is designated Not Applicable by the PALB2 VCEP (v1.2.0).	cspec
BS4	Not met	No segregation data demonstrating lack of co-segregation (LOD ≤ -0.32 or Bayes Factor ≤0.48) with disease is available for this variant.	cspec
BP1	N/A	BP1 under the PALB2 VCEP (v1.2.0) applies to all missense variants only; this is a frameshift duplication.	cspec
BP2	N/A	BP2 is designated Not Applicable by the PALB2 VCEP (v1.2.0).	cspec
BP3	N/A	BP3 is designated Not Applicable by the PALB2 VCEP (v1.2.0): small in-frame losses are neither confirmed nor refuted as a mechanism of pathogenicity, and PALB2 does not have repetitive regions without known function.	cspec
BP4	N/A	Under the PALB2 VCEP (v1.2.0), BP4 for splice predictions cannot be applied in addition to PVS1, which has been assigned for this frameshift variant. Additionally, BP4 is applicable only to splicing variants with SpliceAI ≤0.1.	spliceai cspec
BP5	N/A	BP5 is designated Not Applicable by the PALB2 VCEP (v1.2.0): cases with multiple pathogenic variants have been observed with no noticeable phenotype difference, and PALB2 has moderate penetrance.	cspec
BP6	N/A	BP6 is designated Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 under the PALB2 VCEP (v1.2.0) applies to synonymous and deep intronic variants only; this is a frameshift duplication.	cspec

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