About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.928A>G, p.(Ser310Gly)
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
BS1Strong
BS1 · strong
PALB2 VCEP assigns BS1 (Strong) when grpmax Filtering AF >0.01% in gnomAD v4. The grpmax FAF in gnomAD v4.1 is 0.015106%, which exceeds the VCEP threshold. The variant is observed in 206/1,614,002 alleles (AF=0.01276%) in gnomAD v4.1, predominantly in the European (non-Finnish) population (201/1,179,992 alleles).
BP1Supporting
BP1 · supporting
PALB2 VCEP assigns BP1 (Supporting) to all missense variants in PALB2, given the very low likelihood that missense variants in this gene are pathogenic. NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP1 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
206 / 1,614,002 alleles
gnomAD v4.1: 206 / 1,614,002 alleles. Recorded AF 0.000127633. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.77753e-05; MAF= 0.00478%, 12/251176 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000105619; MAF= 0.01056%, 12/113616 alleles, homozygotes = 0); grpmax FAF= 6.019e-05.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
11 reported laboratory submissions
8 Uncertain significance · 2 Likely benign · 1 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55167149, n = 1 times).
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 · 6 not met · 0 not assessed · 18 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.928A>G (p.Ser310Gly) is a missense variant in PALB2, a gene in which primarily truncating variants are known to cause disease and missense pathogenic variation is not yet confirmed as a disease mechanism (VCEP v1.2.0).
The variant is present in gnomAD v4.1 at an overall allele frequency of 0.01276% (206/1,614,002 alleles, 0 homozygotes) with a grpmax filtering AF of 0.015106% in the European (non-Finnish) population. This exceeds the PALB2 VCEP BS1 threshold of >0.01%, supporting a benign interpretation at Strong strength.
SpliceAI predicts no significant splice impact (max delta score = 0.02), consistent with a missense change without cryptic splice effects.
REVEL score is 0.034 and BayesDel score is -0.732, consistent with a benign in silico profile, though computational predictors have not been validated for PALB2 missense variant functional outcome per the VCEP.
BP1 (Supporting) is applied per the PALB2 VCEP, which assigns this code to all missense variants given the very low prior probability that PALB2 missense variants are pathogenic.
Combining BS1 (Strong benign) with BP1 (Supporting benign) yields a classification of Likely Benign per the ACMG/AMP combination rules adopted by the PALB2 VCEP (Rule 20: ≥1 Benign Strong criterion).
No criteria match.
Met · 2
BS1 StrongPALB2 VCEP assigns BS1 (Strong) when grpmax Filtering AF >0.01% in gnomAD v4. The grpmax FAF in gnomAD v4.1 is 0.015106%, which exceeds the VCEP threshold. The variant is observed in 206/1,614,002 alleles (AF=0.01276%) in gnomAD v4.1, predominantly in the European (non-Finnish) population (201/1,179,992 alleles). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: grpmax FAF = 0.015106% (>0.01% VCEP threshold for BS1 Strong). 206 total alleles observed
- 0 homozygotes.
Sources
BP1 SupportingPALB2 VCEP assigns BP1 (Supporting) to all missense variants in PALB2, given the very low likelihood that missense variants in this gene are pathogenic. NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant. Details ▾Hide ▴
Evidence considered
- VCEP BP1: 'Apply to all missense variants' at Supporting strength. This is a missense variant (p.Ser310Gly).
Sources
Not met · 6 · evaluated, threshold not reached
PS4 PALB2 VCEP requires case-control studies with p≤0.05 AND (OR≥3 OR lower 95% CI≥1.5). No published case-control data meeting this statistical threshold has been identified for NM_024675.4:c.928A>G. Details ▾Hide ▴
Evidence considered
- VCEP PS4 requires case-control enrichment data
- no qualifying study found for this variant.
Still missing
- No case-control odds ratio or enrichment data available for this variant.
Sources
PM2 PALB2 VCEP assigns PM2_Supporting when gnomAD v4 frequency ≤0.000333% (1/300,000). The grpmax filtering AF in gnomAD v4.1 is 0.015106% (0.00015106), which exceeds this threshold. PM2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.00015106 (0.015106%)
- exceeding the VCEP PM2 threshold of 0.000333%.
Sources
PP1 No segregation data (LOD score or co-occurrence in affected relatives) has been published for NM_024675.4:c.928A>G. PALB2 VCEP requires quantitative co-segregation analysis. Details ▾Hide ▴
Evidence considered
- No published segregation analysis for this variant in AD or AR context.
Still missing
- No family segregation or LOD score data available.
Sources
BA1 PALB2 VCEP requires grpmax Filtering AF >0.1% in gnomAD v4. The observed grpmax FAF in gnomAD v4.1 is 0.015106%, which does not exceed the 0.1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 0.015106%
- below the VCEP BA1 threshold of >0.1%.
Sources
BS2 PALB2 VCEP BS2 applies to Fanconi Anemia (recessive) probands observed in trans with a pathogenic variant without meeting FA phenotype. No such proband data is available for NM_024675.4:c.928A>G. Details ▾Hide ▴
Evidence considered
- No Fanconi Anemia proband data available for BS2 point assignment.
Still missing
- No FA proband data available.
Sources
BS4 PALB2 VCEP requires quantitative co-segregation analysis (LOD score or Bayes Factor) demonstrating lack of segregation. No such data is available for NM_024675.4:c.928A>G. Details ▾Hide ▴
Evidence considered
- No family non-segregation data or LOD scores available for this variant.
Still missing
- No quantitative co-segregation or lack-of-segregation data.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is restricted to null variants (nonsense, frameshift, canonical splice ±1/2, initiation codon, full gene deletion) per the PALB2 VCEP PVS1 Decision Tree. NM_024675.4:c.928A>G (p.Ser310Gly) is a missense variant and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant at codon 310
- not a null variant eligible for PVS1 under the PALB2 VCEP decision tree.
Sources
cspec ↗pvs1_variant_assessment
PS1 N/APALB2 VCEP restricts PS1 to splicing variants via the PALB2 PS1 Splicing table; missense variants are explicitly excluded per VCEP instruction: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' Details ▾Hide ▴
Evidence considered
- VCEP PS1 instruction: missense variants excluded
- splicing-only criterion for PALB2.
Sources
PS2 VCEPPALB2 VCEP states PS2 is not applicable: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.' Details ▾Hide ▴
PS3 VCEPPALB2 VCEP states PS3 is not applicable. Details ▾Hide ▴
PM1 VCEPPALB2 VCEP states PM1 is not applicable: 'Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' Details ▾Hide ▴
Evidence considered
- VCEP PM1 applicability: Not applicable
- missense pathogenicity not confirmed for PALB2.
Sources
PM5 N/APALB2 VCEP states: 'Do not use for missense changes: Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PM5_Supporting is restricted to frameshifting/truncating variants with PTC upstream of p.Tyr1183 and qualifying splice variants. Details ▾Hide ▴
PM6 VCEPPALB2 VCEP states PM6 is not applicable: 'Informative de novo occurrences have not yet been observed.' Details ▾Hide ▴
PP2 VCEPPALB2 VCEP states PP2 is not applicable: 'Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' Details ▾Hide ▴
Evidence considered
- VCEP PP2 applicability: Not applicable
- missense mechanism not confirmed for PALB2.
Sources
PP3 N/APALB2 VCEP states for PP3: 'Missense: Do not use.' The splicing sub-rule (SpliceAI ≥0.2) does not apply because SpliceAI max delta is 0.02 and the VCEP explicitly excludes missense variants from PP3. Details ▾Hide ▴
Evidence considered
- VCEP PP3 instruction: missense excluded. SpliceAI max delta = 0.02
- below the 0.2 threshold for splicing PP3 in any case.
Sources
PP4 VCEPPALB2 VCEP states PP4 is not applicable: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology.' Details ▾Hide ▴
Evidence considered
- VCEP PP4 applicability: Not applicable for PALB2 autosomal dominant condition.
Sources
PP5 VCEPPALB2 VCEP states PP5 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 VCEPPALB2 VCEP states BS3 is not applicable. Details ▾Hide ▴
BP2 VCEPPALB2 VCEP states BP2 is not applicable. Details ▾Hide ▴
BP4 N/APALB2 VCEP states for BP4: 'Missense: Do not use.' The splicing sub-rule (SpliceAI ≤0.1) also states 'Do not apply for missense variants.' Details ▾Hide ▴
Evidence considered
- VCEP BP4 instruction: missense excluded. SpliceAI max delta = 0.02 confirms no splice impact
- but BP4 is not applied to missense variants per VCEP.
Sources
BP5 VCEPPALB2 VCEP states BP5 is not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and PALB2 has moderate penetrance. Details ▾Hide ▴
BP6 VCEPPALB2 VCEP states BP6 is 'Not Applicable for this VCEP' as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 is applicable only to synonymous and deep intronic variants per the PALB2 VCEP. NM_024675.4:c.928A>G is a missense variant (p.Ser310Gly). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous and deep intronic variants.
Sources
PS5 N/APS5 is not a standard ACMG/AMP criterion. The equivalent criterion PP5 is designated 'Not Applicable for this VCEP' per the PALB2 VCEP. Details ▾Hide ▴
Evidence considered
- PS5 not defined in ACMG/AMP 2015 framework
- PP5 equivalent marked not applicable by VCEP.
Sources
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.928A>G
- Protein (HGVS p.)
- NP_078951.2:p.(Ser310Gly)
- GRCh38
- chr16:23635618 T>C
- GRCh37
- chr16:23646939 T>C
- ClinVar
- 128149
- COSMIC
- COSV55167149
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
206 / 1,614,002 alleles
AF 0.000128 · 0 homozygotes · FAF 0.000151
gnomAD v2.1
12 / 251,176 alleles
AF 4.78e-05 · 0 homozygotes · FAF 6.02e-05
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.00013 · 206 / 1,614,002 alleles · 0 hom · FAF 0.00015
| European (non-Finnish)201 / 1,179,992 | 0.00017 |
| Remaining individuals5 / 62,480 | 8e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4.8e-05 · 12 / 251,176 alleles · 0 hom · FAF 6e-05
| European (non-Finnish)12 / 113,616 | 0.00011 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000127633; MAF= 0.01276%, 206/1614002 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00017034; MAF= 0.01703%, 201/1179992 alleles, homozygotes = 0); grpmax FAF= 0.00015106.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.77753e-05; MAF= 0.00478%, 12/251176 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000105619; MAF= 0.01056%, 12/113616 alleles, homozygotes = 0); grpmax FAF= 6.019e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.034
- BayesDel
- -0.732
How the predictions were used
PP3 N/APALB2 VCEP states for PP3: 'Missense: Do not use.' The splicing sub-rule (SpliceAI ≥0.2) does not apply because SpliceAI max delta is 0.02 and the VCEP explicitly excludes missense variants from PP3. Details ▾Hide ▴
Evidence considered
- VCEP PP3 instruction: missense excluded. SpliceAI max delta = 0.02
- below the 0.2 threshold for splicing PP3 in any case.
Sources
BP4 N/APALB2 VCEP states for BP4: 'Missense: Do not use.' The splicing sub-rule (SpliceAI ≤0.1) also states 'Do not apply for missense variants.' Details ▾Hide ▴
Evidence considered
- VCEP BP4 instruction: missense excluded. SpliceAI max delta = 0.02 confirms no splice impact
- but BP4 is not applied to missense variants per VCEP.
Sources
BP7 N/ABP7 is applicable only to synonymous and deep intronic variants per the PALB2 VCEP. NM_024675.4:c.928A>G is a missense variant (p.Ser310Gly). Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 restricted to synonymous and deep intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.034. BayesDel score = -0.732133.
9 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.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 26635394 ↗RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins.Mao F et al. · 2016No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.No paper-specific finding is recorded.
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PMID 17200668 ↗PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.Rahman N et al. · 2007No paper-specific finding is recorded.
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.No paper-specific finding is recorded.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.No paper-specific finding is recorded.
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PMID 20301425 ↗PMID:20301425No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
206 / 1,614,002 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
8 Uncertain significance · 2 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/128149/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23646939-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635618-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.928A…
- OncoKB ↗www.oncokb.org/gene/PALB2/S310G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120586187
- 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= 0.000127633; MAF= 0.01276%, 206/1614002 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00017034; MAF= 0.01703%, 201/1179992 alleles, homozygotes = 0); grpmax FAF= 0.00015106.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.77753e-05; MAF= 0.00478%, 12/251176 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000105619; MAF= 0.01056%, 12/113616 alleles, homozygotes = 0); grpmax FAF= 6.019e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 128149)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.034. BayesDel score = -0.732133.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55167149, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.