About PALB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PALB2 c.740C>G, p.(Thr247Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
PALB2 VCEP v1.2.0: 'Apply to all missense variants' at Supporting strength. Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays; true missense pathogenic variants are thought to be exceedingly rare. This missense variant (p.Thr247Arg) is eligible for BP1_Supporting.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BP1 supporting benign; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
No screenshot for this evidence
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD-Canada
Absent from 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.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
8 reported laboratory submissions
7 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
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
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.
27 criteria with recorded statuses: 1 met · 4 not met · 5 not assessed · 17 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.740C>G (p.Thr247Arg) is a missense variant in exon 4 of PALB2 identified in 1 of 1996 Australian familial breast cancer cases and 0 of 1998 cancer-free controls (Thompson et al. 2015).
Under the ClinGen PALB2 VCEP v1.2.0 framework, most pathogenic criteria are not applicable to missense variants: PVS1 (null variant only), PS1 (missense excluded), PM1 (missense excluded), PM5 (truncating only), PP2 (missense excluded), PP3/BP4 (missense excluded). PS3/BS3 are not applicable per VCEP.
BP1_Supporting is met: the PALB2 VCEP applies BP1 to all missense variants at Supporting level, reflecting the very low likelihood that missense variants in PALB2 are pathogenic based on published functional data.
PM2 could not be assessed: gnomAD v4 frequency data is unavailable (scrape timed out). The variant has an rsID (rs587782658) and is present in population databases, but the exact allele frequency needed for the VCEP PM2_Supporting threshold (≤0.000333%) requires manual confirmation.
PS4 is not met: the single case observation (1/1996 cases vs 0/1998 controls) does not constitute a statistically significant case-control enrichment (p=0.48, Fisher's exact test).
No functional data (PS3 not applicable per VCEP), no segregation data (PP1/BS4 not assessed), no de novo reports (PS2/PM6 not applicable), and no Fanconi Anemia observations (BS2 not assessed) are available for this variant.
In silico predictors are mixed: REVEL score 0.065 and BayesDel -0.512 are benign-leaning; SpliceAI delta 0.00 predicts no splice impact. However, under VCEP rules, PP3 and BP4 are not applicable for missense variants regardless of predictor scores.
ClinVar classification is Uncertain significance (7 clinical laboratories) / Likely benign (1 laboratory), with no expert panel review. This is consistent with the limited evidence available for this missense variant.
No criteria match.
Met · 1
BP1 SupportingPALB2 VCEP v1.2.0: 'Apply to all missense variants' at Supporting strength. Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays; true missense pathogenic variants are thought to be exceedingly rare. This missense variant (p.Thr247Arg) is eligible for BP1_Supporting. Details ▾Hide ▴
Evidence considered
- VCEP BP1 rule: applicable to all PALB2 missense variants at Supporting level.
Sources
Not met · 4 · evaluated, threshold not reached
PS4 The variant was observed in 1 of 1996 familial breast cancer cases and 0 of 1998 controls in Thompson et al. 2015 (PMID:26283626) — a single observation insufficient to meet VCEP PS4 requirements (case-control study with p≤0.05 AND OR≥3 OR lower 95% CI≥1.5). No other case-control enrichment data identified. Details ▾Hide ▴
Evidence considered
- Observed in 1/1996 cases vs 0/1998 controls in Thompson et al. 2015 — single observation
- not statistically significant enrichment.
Still missing
- Larger case-control studies needed for statistical power.
Sources
BA1 PALB2 VCEP BA1 requires Grpmax Filtering AF >0.1% in gnomAD v4. While gnomAD v4 data timed out, the variant was absent from gnomAD-Canada (0 carriers) and was found in only 1 of 3994 individuals (0.025%) in the Thompson et al. 2015 case-control cohort. Available evidence is inconsistent with a population frequency >0.1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD-Canada. Found in 1/3994 (0.025%) in Thompson et al. 2015 cohort.
Still missing
- gnomAD v4 frequency confirmation pending (scrape timed out).
Sources
BP7 PALB2 VCEP BP7 applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). This is a missense variant (c.740C>G, p.Thr247Arg), not synonymous. No RNA-level data available to assess BP7_RNA for aberrant splicing. SpliceAI predicts no splice impact (delta=0.00) but this does not qualify for BP7 which is for silent/intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- not eligible for BP7 (synonymous only). No RNA data for BP7_RNA.
Sources
PS5 No reputable source (e.g., expert panel, clinical guideline) has reported this variant as pathogenic. ClinVar classification is Uncertain significance (7 labs) / Likely benign (1 lab); no expert panel classification exists. Details ▾Hide ▴
Evidence considered
- ClinVar: 7 US
- 1 LB. No expert panel classification. No reputable source reports as pathogenic.
Sources
Not assessed · 5 · no assessment recorded
PM2 PALB2 VCEP PM2_Supporting requires frequency ≤0.000333% in gnomAD v4. The gnomAD v4 scrape for this variant timed out (120s) during evidence gathering. The variant has an rsID (rs587782658) and Invitae's ClinVar submission notes it is present in population databases, but the exact gnomAD v4 allele frequency could not be confirmed. Manual lookup required. Details ▾Hide ▴
Evidence considered
- gnomAD v4 data unavailable (timeout)
- rs587782658 present in dbSNP
- Invitae notes variant present in population databases.
Still missing
- Need gnomAD v4 allele frequency to determine if PM2_Supporting threshold (≤0.000333%) is met.
PP1 No co-segregation data or family studies evaluating NM_024675.4:c.740C>G were identified in the literature or evidence packet. Thompson et al. 2015 reported a single carrier among 1996 cases; no family segregation analysis was performed. Details ▾Hide ▴
Evidence considered
- No segregation data available for this variant.
Still missing
- Need co-segregation analysis in families carrying this variant.
BS1 PALB2 VCEP BS1 requires Grpmax Filtering AF >0.01% in gnomAD v4. gnomAD v4 scrape timed out. The variant has an rsID (rs587782658) and is present in population databases per ClinVar/Invitae, but exact frequency is unknown. Manual lookup needed. Details ▾Hide ▴
Evidence considered
- gnomAD v4 data unavailable (timeout). rs587782658 exists
- variant present in population databases per ClinVar.
Still missing
- Need gnomAD v4 Grpmax Filtering AF to determine if BS1 threshold (>0.01%) is met.
BS2 PALB2 VCEP BS2 requires Fanconi Anemia proband scoring. No Fanconi Anemia cases with this variant were identified in the evidence packet. BS2 requires curated phenotype data not available in this data pull. Details ▾Hide ▴
Evidence considered
- No Fanconi Anemia proband data available.
Still missing
- Need Fanconi Anemia proband data to apply BS2 point system.
BS4 No co-segregation or family study data available for this variant. BS4 requires quantitative segregation analysis (LOD scores). The single carrier identified in Thompson et al. 2015 had no accompanying family segregation data. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Need quantitative co-segregation analysis (LOD scores).
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_024675.4:c.740C>G is a missense variant (p.Thr247Arg). PVS1 applies only to null variants (nonsense, frameshift, canonical splice sites). This variant does not fall into any PVS1-eligible null-variant bucket. Details ▾Hide ▴
PS1 N/APALB2 VCEP v1.2.0 specifies: 'Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.' PS1 is restricted to splicing variants via the PALB2 PS1 Splicing table; missense variants are explicitly excluded. Details ▾Hide ▴
PS2 VCEPPALB2 VCEP v1.2.0: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.' PS2 is not applicable for PALB2 under this VCEP. Details ▾Hide ▴
PS3 VCEPPALB2 VCEP v1.2.0 declares PS3 not applicable for protein-level functional studies in PALB2. No variant-specific functional data identified in the literature; OncoKB records this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. Details ▾Hide ▴
PM1 VCEPPALB2 VCEP v1.2.0: 'Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.' PM1 is explicitly excluded for missense variants in PALB2 under this VCEP. Details ▾Hide ▴
PM5 N/APALB2 VCEP v1.2.0 PM5 applies only to frameshifting/truncating variants with premature termination codons upstream of p.Tyr1183, and to splice variants where PVS1 is applied. Missense variants are explicitly excluded: 'Do not use for missense changes.' PM5 candidates artifact confirms this is a truncation-cutoff rule. Details ▾Hide ▴
Evidence considered
- VCEP PM5 rule is for truncating variants
- missense excluded.
Sources
cspec ↗pm5_candidates
PM6 VCEPPALB2 VCEP v1.2.0: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.' PM6 is not applicable for PALB2 under this VCEP. Details ▾Hide ▴
PP2 VCEPPALB2 VCEP v1.2.0: 'Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2.' PP2 is not applicable for PALB2 missense variants. Details ▾Hide ▴
PP3 N/APALB2 VCEP v1.2.0: 'Missense: Do not use.' PP3 is restricted to splicing variants with SpliceAI ≥0.2. SpliceAI max delta score is 0.00 for this variant, confirming no predicted splice impact. REVEL (0.065) and BayesDel (-0.512) scores are both in the benign range, but in silico missense predictors are explicitly excluded from PP3 under this VCEP. Details ▾Hide ▴
Evidence considered
- VCEP excludes PP3 for missense
- SpliceAI=0.00
- REVEL=0.065
- BayesDel=-0.512.
Sources
PP4 VCEPPALB2 VCEP v1.2.0: 'Do not use for AD disorder as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.' PP4 is not applicable for PALB2. Details ▾Hide ▴
PP5 VCEPPALB2 VCEP v1.2.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' PP5 is not applicable for this VCEP. Details ▾Hide ▴
BS3 VCEPPALB2 VCEP v1.2.0: Not applicable. The VCEP redirects protein-level functional analyses to PVS1/BP7 modulation and does not use BS3. Details ▾Hide ▴
BP2 VCEPPALB2 VCEP v1.2.0: 'Use ATM PM3/BP2 table.' BP2 is not applicable under the PALB2 VCEP — the VCEP redirects to the ATM-specific BP2 framework. Details ▾Hide ▴
BP3 VCEPSkipped per instructions: trivially not_applicable for substitution variant. Details ▾Hide ▴
Evidence considered
- Trivially not applicable for substitution variant.
BP4 N/APALB2 VCEP v1.2.0: 'Missense: Do not use.' BP4 is restricted to splicing variants with SpliceAI ≤0.1; missense variants are explicitly excluded. SpliceAI max delta is 0.00, confirming no predicted splice impact, but BP4 cannot be applied to missense under this VCEP. Details ▾Hide ▴
BP5 VCEPPALB2 VCEP v1.2.0: Not applicable. VCEP rationale: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; PALB2 has moderate penetrance and will naturally occur with other pathogenic variants. Details ▾Hide ▴
BP6 VCEPPALB2 VCEP v1.2.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' BP6 is not applicable for this VCEP. Details ▾Hide ▴
Identifiers
- Gene
- PALB2
- Transcript
- NM_024675.4
- Coding (HGVS c.)
- NM_024675.4:c.740C>G
- Protein (HGVS p.)
- NP_078951.2:p.(Thr247Arg)
- GRCh38
- chr16:23635806 G>C
- GRCh37
- chr16:23647127 G>C
- ClinVar
- 142706
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.065
- BayesDel
- -0.512
How the predictions were used
BP7 PALB2 VCEP BP7 applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). This is a missense variant (c.740C>G, p.Thr247Arg), not synonymous. No RNA-level data available to assess BP7_RNA for aberrant splicing. SpliceAI predicts no splice impact (delta=0.00) but this does not qualify for BP7 which is for silent/intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- not eligible for BP7 (synonymous only). No RNA data for BP7_RNA.
Sources
PP3 N/APALB2 VCEP v1.2.0: 'Missense: Do not use.' PP3 is restricted to splicing variants with SpliceAI ≥0.2. SpliceAI max delta score is 0.00 for this variant, confirming no predicted splice impact. REVEL (0.065) and BayesDel (-0.512) scores are both in the benign range, but in silico missense predictors are explicitly excluded from PP3 under this VCEP. Details ▾Hide ▴
Evidence considered
- VCEP excludes PP3 for missense
- SpliceAI=0.00
- REVEL=0.065
- BayesDel=-0.512.
Sources
BP4 N/APALB2 VCEP v1.2.0: 'Missense: Do not use.' BP4 is restricted to splicing variants with SpliceAI ≤0.1; missense variants are explicitly excluded. SpliceAI max delta is 0.00, confirming no predicted splice impact, but BP4 cannot be applied to missense under this VCEP. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.065. BayesDel score = -0.511995.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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 guidelines for interpretation of sequence variants (Richards et al. 2015). This is the foundational standards document establishing the ACMG/AMP classification framework; it does not mention any specific PALB2 variants.Does not name this variant
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PMID 28779002 ↗Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.Decker B et al. · 2017This study evaluated rare protein-truncating variants in ATM, CHEK2, PALB2, and XRCC2 in 13,087 breast cancer cases and 5,488 controls. NM_024675.4:c.740C>G is a missense variant and was not within the scope of this paper's truncating-variant analysis.Does not name this variant
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PMID 34242744 ↗Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.St. Gallen International Consensus Guidelines for treatment of early breast cancer (2021). This is a breast cancer treatment consensus guideline; no specific PALB2 variants are discussed and c.740C>G is not mentioned.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 entry on BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. No abstract or full text available in case packet, but this is a BRCA1/BRCA2-focused resource; PALB2 variant c.740C>G is not expected to be discussed.Does not name this variant
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PMID 24366376 ↗Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.USPSTF recommendation statement on BRCA-related cancer risk assessment, genetic counseling, and genetic testing. This guideline addresses BRCA1/BRCA2 screening; PALB2 and the variant c.740C>G are not discussed.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. This document provides general referral criteria for hereditary cancer syndromes; no specific PALB2 variants are discussed.Does not name this variant
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PMID 26283626 ↗Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.Thompson ER et al. · 2015NM_024675.3:c.740C>G (p.Thr247Arg) was detected in 1 of 1996 Australian familial breast cancer index cases and 0 of 1998 cancer-free controls. CADD score 15.5; Condel: Deleterious; PolyPhen2: Probably damaging; SIFT: Tolerated. The paper concluded no excess of missense mutations overall in cancer cases and advised extreme caution in attributing risk to PALB2 missense variants.Names this variant
Quoted passage
4 c.740C > G p.Thr247Arg . . . . . 1 15.5 Deleterious Probably damaging Tolerated
Results; Table 3 (Missense variants)
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PMID 26315354 ↗Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.Ramus SJ et al. · 2015This study evaluated germline truncating mutations in BRIP1, BARD1, PALB2, and NBN in ovarian cancer cases and controls. NM_024675.4:c.740C>G is a missense variant and was not reported or analyzed in this paper, which focused exclusively on protein-truncating variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
7 Uncertain significance · 1 Likely 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/142706/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-23647127-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-23635806-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-23635806-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024675.4%3Ac.740C…
- OncoKB ↗www.oncokb.org/gene/PALB2/T247R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PALB2+c.740C%3EG
- 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-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 142706)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.065. BayesDel score = -0.511995.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.