About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.1209G>A, p.(Leu403=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PALB2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤0.1 VCEP threshold). Per PALB2 VCEP v1.2.0, BP4_Supporting may be applied for splicing assessment when SpliceAI ≤0.1.
BP7Supporting
BP7 · supporting
NM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=) located in exon 4 at position c.1209, far from splice donor (475 nt from +1) and acceptor (997 nt from -1) sites. SpliceAI predicts no splicing impact (max delta = 0.00). Per PALB2 VCEP v1.2.0, BP7_Supporting applies to synonymous variants beyond ±7/21 of splice consensus sites.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
7 / 1,614,016 alleles
gnomAD v4.1: 7 / 1,614,016 alleles. Recorded AF 4.33701e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.986e-06; MAF= 0.00040%, 1/250878 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82426e-06; MAF= 0.00088%, 1/113324 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
7 reported laboratory submissions
6 Likely benign · 1 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.2.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 10 not met · 0 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_024675.4:c.1209G>A (p.Leu403=) is a synonymous variant in exon 4 of PALB2 with no predicted splicing impact (SpliceAI max delta 0.00), meeting BP7_Supporting per PALB2 VCEP v1.2.0.
SpliceAI predicts no splicing impact (max delta 0.00, below VCEP threshold of 0.1), meeting BP4_Supporting per PALB2 VCEP v1.2.0.
The variant is present in gnomAD v4.1 at a total allele frequency of 4.34×10⁻⁶ (7/1,614,016 alleles, grpmax FAF 7.9×10⁻⁷), exceeding the VCEP PM2_Supporting threshold of 3.33×10⁻⁶; PM2 is not met.
ClinVar reports this variant as Likely benign (6 clinical laboratories) and Benign (1 clinical laboratory); no expert panel has classified it as pathogenic (VariationID: 185784).
No published literature was identified that directly references NM_024675.4:c.1209G>A. Eight papers retrieved from ClinVar and OncoKB sources were reviewed; none mention the specific variant.
No criteria match.
Met · 2
BP4 SupportingSpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤0.1 VCEP threshold). Per PALB2 VCEP v1.2.0, BP4_Supporting may be applied for splicing assessment when SpliceAI ≤0.1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- VCEP BP4 splicing threshold: SpliceAI ≤ 0.1 (met)
Sources
BP7 SupportingNM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=) located in exon 4 at position c.1209, far from splice donor (475 nt from +1) and acceptor (997 nt from -1) sites. SpliceAI predicts no splicing impact (max delta = 0.00). Per PALB2 VCEP v1.2.0, BP7_Supporting applies to synonymous variants beyond ±7/21 of splice consensus sites. Details ▾Hide ▴
Evidence considered
- Synonymous substitution p.(Leu403=)
- Located deep in exon 4
- far from splice boundaries (475 nt from donor
- 997 nt from acceptor)
- SpliceAI max delta = 0.00 — no predicted splice alteration
Sources
Not met · 10 · evaluated, threshold not reached
PS4 No case-control study data are available for NM_024675.4:c.1209G>A. PS4 requires a study with p≤0.05 and OR≥3 (or lower 95% CI≥1.5). This variant is reported in ClinVar as Likely benign/Benign by 7 clinical laboratories but lacks the controlled epidemiological data required. Details ▾Hide ▴
PM2 The gnomAD v4.1 total allele frequency is 4.34×10⁻⁶ (7/1,614,016 alleles), which exceeds the PALB2 VCEP PM2_Supporting threshold of ≤3.33×10⁻⁶ (≤0.000333%, 1/300,000). PM2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 4.34×10⁻⁶ (7/1
- 614
- 016 alleles
- grpmax FAF = 7.9×10⁻⁷)
- VCEP PM2 threshold: ≤ 3.33×10⁻⁶ (≤ 0.000333%)
- Frequency exceeds threshold
Sources
PP1 No co-segregation data are available for NM_024675.4:c.1209G>A. Per VCEP, quantitative co-segregation analysis is required; no LOD score or affected-relative data have been provided. Details ▾Hide ▴
Evidence considered
- No co-segregation data available
Still missing
- No family segregation data
Sources
PP3 Per VCEP, PP3 is not used for missense variants and requires SpliceAI ≥0.2 for splicing assessment. This synonymous variant has SpliceAI max delta 0.00, well below the threshold. No pathogenic in silico signal is present. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- VCEP PP3 threshold: SpliceAI ≥ 0.2 (not met)
- REVEL/BayesDel not available for synonymous variant
Sources
BA1 The gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷ (0.000079%), far below the PALB2 VCEP BA1 threshold of >0.1%. BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 7.9×10⁻⁷ (0.000079%)
- VCEP BA1 threshold: > 0.1%
Sources
BS1 The gnomAD v4.1 grpmax filtering allele frequency is 7.9×10⁻⁷ (0.000079%), below the PALB2 VCEP BS1 threshold of >0.01%. BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 7.9×10⁻⁷ (0.000079%)
- VCEP BS1 threshold: > 0.01%
Sources
BS2 No proband-level data are available for BS2 assessment. Per VCEP, BS2 requires counting affected probands using Fanconi Anemia BS2 tables; no individual-level phenotype or genotype data have been provided to calculate BS2 points. Details ▾Hide ▴
Evidence considered
- No proband-level data available for Fanconi Anemia BS2 point calculation
Still missing
- No proband phenotype/genotype data
Sources
BS4 No co-segregation data are available to calculate a LOD score or Bayes Factor for lack of segregation. Per VCEP, quantitative co-segregation analysis is required; no such data have been provided. Details ▾Hide ▴
Evidence considered
- No co-segregation data available for BS4 LOD assessment
Still missing
- No family segregation data for lack-of-segregation analysis
Sources
BP1 Per VCEP, BP1 applies to all missense variants in PALB2 (low rate of functional missense variants). NM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=), not a missense variant. BP1 does not apply. Details ▾Hide ▴
Evidence considered
- Synonymous substitution (p.Leu403=)
- VCEP BP1 is restricted to missense variants only
Sources
PS5 No reputable source has reported NM_024675.4:c.1209G>A as pathogenic. ClinVar reports Likely benign (6 clinical labs) and Benign (1 clinical lab). No expert panel has classified this variant as pathogenic. Details ▾Hide ▴
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The PALB2 VCEP PVS1 Decision Tree is designed for truncating and splice-altering variants. Details ▾Hide ▴
Evidence considered
- Synonymous substitution
- no predicted splice impact (SpliceAI max delta = 0.00)
- Variant does not meet PVS1 null-variant criteria per ClinGen SVI PVS1 framework (PMC6185798)
Sources
PS1 N/APer PALB2 VCEP v1.2.0, PS1 is not used for missense variants and is applied only to splicing variants via the PALB2 PS1 Splicing table. This synonymous variant has no splice impact (SpliceAI max delta 0.00) and is neither missense nor splicing-altering. Details ▾Hide ▴
Evidence considered
- Synonymous variant with SpliceAI max delta 0.00
- VCEP PS1 rules cover missense (not used) and splicing (not applicable here) only
Sources
PS2 VCEPVCEP specifies PS2 is not applicable for PALB2; de novo occurrences are not yet observed for autosomal dominant PALB2-related disease. Details ▾Hide ▴
PS3 VCEPVCEP specifies PS3 is not applicable for PALB2; functional protein assays are not validated for PALB2 missense assessment. Details ▾Hide ▴
PM1 VCEPVCEP specifies PM1 is not applicable for PALB2; missense pathogenic variation is not yet confirmed as a mechanism of disease. Details ▾Hide ▴
PM5 N/APer PALB2 VCEP v1.2.0, PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, or to splice variants. This is a synonymous variant and does not meet either criterion. PM5 is additionally not used for missense changes per VCEP. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- VCEP PM5 restricted to truncating/frameshift/splice upstream of p.Tyr1183
Sources
cspec ↗pm5_candidates
PM6 VCEPVCEP specifies PM6 is not applicable for PALB2; informative de novo occurrences have not yet been observed for autosomal dominant PALB2-related disease. Details ▾Hide ▴
PP2 VCEPVCEP specifies PP2 is not applicable for PALB2; missense is not yet confirmed or refuted as a mechanism of disease. Details ▾Hide ▴
PP4 VCEPVCEP specifies PP4 is not applicable for PALB2 autosomal dominant disease; breast cancer has multiple genetic etiologies and no features reliably distinguish hereditary from sporadic cases. Details ▾Hide ▴
PP5 VCEPVCEP specifies PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 VCEPVCEP specifies BS3 is not applicable for PALB2; for RNA, use BP7(RNA) instead. For protein, assays are not validated for PALB2 missense assessment. Details ▾Hide ▴
BP2 VCEPVCEP specifies BP2 is not applicable for PALB2; use ATM PM3/BP2 table instead. Details ▾Hide ▴
BP5 VCEPVCEP specifies BP5 is not applicable for PALB2; cases with multiple pathogenic variants have been observed without noticeable phenotype differences, and PALB2's moderate penetrance leads to frequent co-occurrence with other pathogenic variants. Details ▾Hide ▴
BP6 VCEPVCEP specifies BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.1209G>A
- Protein (HGVS p.)
- NP_078951.2:p.(Leu403=)
- GRCh38
- chr16:23635337 C>T
- GRCh37
- chr16:23646658 C>T
- ClinVar
- 185784
Gene diagram
Every interpreted variant in PALB2, mapped onto the exon structure of NM_024675.4. Select a row to find it on the plot.
PALB2NM_024675.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PALB2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
7 / 1,614,016 alleles
AF 4.34e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
1 / 250,878 alleles
AF 3.99e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.3e-06 · 7 / 1,614,016 alleles · 0 hom · FAF 7.9e-07
| Middle Eastern1 / 6,060 | 0.00017 |
| Remaining individuals2 / 62,508 | 3.2e-05 |
| European (non-Finnish)4 / 1,180,030 | 3.4e-06 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 250,878 alleles · 0 hom
| European (non-Finnish)1 / 113,324 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.33701e-06; MAF= 0.00043%, 7/1614016 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.986e-06; MAF= 0.00040%, 1/250878 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82426e-06; MAF= 0.00088%, 1/113324 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤0.1 VCEP threshold). Per PALB2 VCEP v1.2.0, BP4_Supporting may be applied for splicing assessment when SpliceAI ≤0.1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- VCEP BP4 splicing threshold: SpliceAI ≤ 0.1 (met)
Sources
BP7 SupportingNM_024675.4:c.1209G>A is a synonymous variant (p.Leu403=) located in exon 4 at position c.1209, far from splice donor (475 nt from +1) and acceptor (997 nt from -1) sites. SpliceAI predicts no splicing impact (max delta = 0.00). Per PALB2 VCEP v1.2.0, BP7_Supporting applies to synonymous variants beyond ±7/21 of splice consensus sites. Details ▾Hide ▴
Evidence considered
- Synonymous substitution p.(Leu403=)
- Located deep in exon 4
- far from splice boundaries (475 nt from donor
- 997 nt from acceptor)
- SpliceAI max delta = 0.00 — no predicted splice alteration
Sources
PP3 Per VCEP, PP3 is not used for missense variants and requires SpliceAI ≥0.2 for splicing assessment. This synonymous variant has SpliceAI max delta 0.00, well below the threshold. No pathogenic in silico signal is present. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- VCEP PP3 threshold: SpliceAI ≥ 0.2 (not met)
- REVEL/BayesDel not available for synonymous variant
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for sequence variant interpretation — a joint consensus recommendation. This foundational framework paper describes ACMG/AMP criteria and classification rules at the methodology level. NM_024675.4:c.1209G>A was not identified.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Describes a standardized DNA variant scoring system (Sherloc) for pathogenicity assessments in Mendelian disorders, analyzing over 16,500 variant assessments across 338 genes. NM_024675.4:c.1209G>A was not identified.Does not name this variant
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004National Society of Genetic Counselors practice guideline on cancer genetic risk assessment and counseling. Discusses general principles of hereditary cancer risk assessment. NM_024675.4:c.1209G>A was not identified.Does not name this variant
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993GeneReviews chapter on BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. Covers BRCA1/2 clinical management. NM_024675.4:c.1209G>A was not identified; PALB2 is outside the scope of this GeneReview.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics Risk Assessment and Counseling summary (Health Professional Version). General overview of cancer genetics risk assessment practice. NM_024675.4:c.1209G>A was not identified.Does not name this variant
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PMID 31429903 ↗Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.USPSTF recommendation statement on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Focuses on BRCA1/2 screening recommendations. NM_024675.4:c.1209G>A was not identified.Does not name this variant
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PMID 31479213 ↗PMID 31479213No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Describes the Sherloc refinement of ACMG-AMP variant classification criteria, a comprehensive rules-based framework. NM_024675.4:c.1209G>A was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
7 / 1,614,016 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
6 Likely benign · 1 Benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1526222356
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/185784/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646658-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635337-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-23635337-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.1209…
- OncoKB ↗www.oncokb.org/gene/PALB2/L403=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.1209G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.33701e-06; MAF= 0.00043%, 7/1614016 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.986e-06; MAF= 0.00040%, 1/250878 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82426e-06; MAF= 0.00088%, 1/113324 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 185784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.