Variant classification summary

NM_024675.3:c.721A>G

PALB2 · NP_078951.2:p.(Asn241Asp) · NM_024675.3

GRCh37: chr16:23647146 T>C · GRCh38: chr16:23635825 T>C

Gene: PALB2 Transcript: NM_024675.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP1 supporting benign BP6 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Asn241Asp)

gnomAD AF

0.0003326799507361086 (v4.1)

ClinVar

Benign

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.721A>G (p.Asn241Asp) missense variant has an allele frequency of 0.63% in the African/African American population in gnomAD v4.1 (472/75,032 alleles) with 3 homozygous individuals observed. The grpmax filtering allele frequency of 0.58% exceeds the PALB2 VCEP BA1 threshold of >0.1%, meeting stand-alone benign criteria.

2

The grpmax filtering allele frequency of 0.58% in gnomAD v4.1 far exceeds the PALB2 VCEP BS1 threshold of >0.01%, providing strong benign evidence. This allele frequency is inconsistent with a highly penetrant pathogenic variant for PALB2-related cancer predisposition.

3

BP1 (supporting benign) is met per PALB2 VCEP v1.2.0, which applies to all PALB2 missense variants given that true missense pathogenic variants are thought to be exceedingly rare in this gene based on published and unpublished functional studies.

4

This variant has been classified as Benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (expert panel review) and is reported as Benign by 9 clinical laboratories and Likely benign by 8 clinical laboratories in ClinVar (VariationID: 126765).

5

SpliceAI predicts no splice impact (max delta score 0.00). REVEL score is 0.013 and BayesDel score is -0.834, consistent with a benign in silico profile, though these predictors are not used for PALB2 missense variants per VCEP guidance.

6

PVS1, PS1, PS3, PM1, PP2, and PP3 are not applicable to this missense variant per PALB2 VCEP v1.2.0. PS4, PM2, PP1, and BS4 are not met due to absence of required evidence. Full-text verification of cited publications was attempted but the retrieved full-text files contained only Sci-Hub interface content rather than actual paper text; citation verification was limited to abstracts.

7

Applying the PALB2 VCEP v1.2.0 final classification rules: BA1 (stand-alone benign) is met, which alone satisfies Rule 17 (>=1 Stand Alone Benign) for a Benign classification. Additionally, BS1 (strong benign) and BP1 (supporting benign) are met, further supporting the benign interpretation.

Final determination: Rule17 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 Benign.

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; this criterion is reserved for null variants (nonsense, frameshift, canonical +/-1,2 splice consensus variants) per the PALB2 PVS1 Decision Tree. This variant is a missense substitution (c.721A>G, p.Asn241Asp).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 per PALB2 VCEP is not applicable to missense variants; missense changes are not yet confirmed as a mechanism of disease for PALB2. The PS1 Splicing table applies only to splicing variants.	cspec
PS2	N/A	PS2 is not applicable per PALB2 VCEP v1.2.0; informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related disease.	cspec
PS3	N/A	PS3 is not applicable per PALB2 VCEP v1.2.0. For protein-level functional studies, the VCEP does not currently endorse PS3 application for PALB2 missense variants.	cspec
PS4	Not met	No case-control study meeting PALB2 VCEP PS4 thresholds (p-value <= 0.05 AND odds ratio >= 3 OR lower 95% CI >= 1.5) has been identified for this variant. The high population frequency (gnomAD v4.1 grpmax FAF 0.58%) makes significant enrichment in affected individuals over controls unlikely. The ClinGen HBOP VCEP expert panel classified this variant as Benign without applying PS4.	gnomad_v4 clinvar
PS5	Not met	No reputable source reports this variant as pathogenic. The ClinVar expert panel (ClinGen HBOP VCEP) classifies it as Benign. Multiple clinical laboratories report it as Benign (9 labs) or Likely benign (8 labs).	clinvar
PM1	N/A	PM1 is not applicable per PALB2 VCEP v1.2.0; missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.	cspec
PM2	Not met	The allele frequency in gnomAD v4.1 is 0.03327% (537/1,614,164 alleles), which far exceeds the PALB2 VCEP PM2_Supporting threshold of <=0.000333% (<=1/300,000). This variant is too common in population databases to apply PM2.	gnomad_v4
PM5	N/A	PM5 per PALB2 VCEP is not applicable to missense variants; it applies only to frameshifting/truncating variants with premature termination codons upstream of p.Tyr1183, or to splice variants meeting specific criteria. Missense changes are not yet confirmed as a mechanism of disease for PALB2.	cspec pm5_candidates
PM6	N/A	PM6 is not applicable per PALB2 VCEP v1.2.0; informative de novo occurrences have not yet been observed for PALB2-related disease.	cspec
PP1	Not met	No co-segregation data meeting PALB2 VCEP PP1 thresholds (LOD >= 0.3 or Bayes Factor >= 2:1 for AD condition) has been identified. Anecdotal reports suggest lack of co-segregation in some families where the variant was observed in unaffected relatives, but no formal quantitative analysis is available.
PP2	N/A	PP2 is not applicable per PALB2 VCEP v1.2.0; missense is not yet confirmed or refuted as a mechanism of disease for PALB2.	cspec
PP3	N/A	PP3 per PALB2 VCEP is not applicable to missense variants; published predictors have not yet achieved reliable functional outcome prediction for PALB2 missense variants. The VCEP specifies PP3 only for splicing variants with SpliceAI >= 0.2. This variant has a SpliceAI max delta score of 0.00.	cspec spliceai
PP4	N/A	PP4 is not applicable per PALB2 VCEP v1.2.0; breast cancer has multiple genetic etiologies and there are no phenotypic features that can readily distinguish hereditary from sporadic causes.	cspec
PP5	N/A	PP5 is not for use per PALB2 VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Met	The grpmax filtering allele frequency in gnomAD v4.1 is 0.58% (FAF 0.00582118), which exceeds the PALB2 VCEP BA1 threshold of >0.1%. This allele frequency is inconsistent with a highly penetrant pathogenic variant for PALB2-related cancer predisposition and meets stand-alone benign criteria.	gnomad_v4
BS1	Met	The grpmax filtering allele frequency in gnomAD v4.1 is 0.58% (FAF 0.00582118), which far exceeds the PALB2 VCEP BS1 threshold of >0.01%. The variant is common in the African/African American population (AF 0.63%) with 3 homozygous individuals observed in gnomAD v4.1, providing strong evidence for a benign interpretation.	gnomad_v4
BS2	Not assessed	BS2 per PALB2 VCEP requires Fanconi Anemia proband data scored via VCEP BS2 tables and explicitly excludes population cohort data such as gnomAD. No Fanconi Anemia proband data was identified for this variant in the evidence reviewed. Although 3 homozygous individuals are observed in gnomAD v4.1, this cannot be used for VCEP BS2 per VCEP instructions.
BS3	N/A	BS3 is not applicable per PALB2 VCEP v1.2.0.	cspec
BS4	Not met	No quantitative co-segregation analysis meeting PALB2 VCEP BS4 thresholds (LOD <= -1.28 for Strong, LOD <= -0.64 for Moderate, LOD <= -0.32 for Supporting) has been identified. Anecdotal reports of non-segregation (variant absent in some affected relatives) exist but lack statistical rigor required for formal BS4 application.
BP1	Met	BP1 applies to all PALB2 missense variants per VCEP guidance: true missense pathogenic variants are thought to be exceedingly rare in PALB2, which has a low rate of non-functional missense variants in relevant assays. This variant is a missense change (p.Asn241Asp).	cspec
BP2	N/A	BP2 is not applicable per PALB2 VCEP v1.2.0.	cspec
BP4	N/A	BP4 per PALB2 VCEP is not applicable to missense variants; published predictors have not yet achieved reliable functional outcome prediction for PALB2 missense variants. The VCEP specifies BP4 only for splicing variants with SpliceAI <= 0.1. Although this variant has a SpliceAI max delta score of 0.00, BP4 is explicitly not for use with missense variants per VCEP.	cspec spliceai revel bayesdel
BP5	N/A	BP5 is not applicable per PALB2 VCEP v1.2.0; PALB2 has moderate penetrance and cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, making this criterion unreliable for PALB2.	cspec
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	BP7 per PALB2 VCEP is applicable to synonymous and deep intronic variants only. This variant is a missense substitution (c.721A>G, p.Asn241Asp), not a synonymous or deep intronic variant.	cspec

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