The PALB2 NM_024675.4:c.110G>A (NP_078951.2:p.(Arg37His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV55166817, n = 2 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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About PALB2
PALB2 encodes a tumor suppressor protein that partners with BRCA2 (and also interacts with BRCA1) to repair double-stranded DNA breaks through the homologous recombination pathway. It acts as a scaffold that stabilizes BRCA2 in the cell nucleus and helps recruit DNA-repair machinery to sites of damage. Inherited mutations in PALB2 increase susceptibility to breast cancer, with smaller associated risks for ovarian, pancreatic, and prostate cancer and melanoma, and inheriting two mutated copies causes Fanconi anemia complementation group N. Rare somatic alterations in PALB2 are also found across various tumor types.
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01The reasoning
How it was classified
The recorded framework is ClinGen PALB2 VCEP v1.3. 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.
Met: case-control comparison gives OR 86.22 (95% CI 11.87–625.98) and Fisher p=0.0118, satisfying the VCEP thresholds OR ≥3 and p≤0.05.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
Met, Supporting: the PALB2 VCEP BP1 rule applies to all missense variants, and c.110G>A produces p.Arg37His.
Recorded classification: Uncertain significance
VUS: PS4 (strong) and BP1 (supporting) are applied, but neither the pathogenic nor benign VCEP combination rules are satisfied.
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
63 / 1,613,090 alleles
gnomAD v4.1: 63 / 1,613,090 alleles. Recorded AF 3.90555e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88912e-05; MAF= 0.00389%, 11/282840 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000150361; MAF= 0.01504%, 3/19952 alleles, homozygotes = 0); grpmax FAF= 4.412e-05.
ACMG/AMP criteria under ClinGen PALB2 VCEP v1.3, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 4 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1, PM4, and BP3 are not applicable under the PALB2 VCEP rules: the variant is missense, while PM4 and BP3 are explicitly marked Not Applicable in the CSPEC.
The governing PALB2_PVS1_v1.3.pdf.txt was searched for c.110G>A, p.Arg37His, and p.R37H; no variant-specific entry was found.
Both requested functional criteria are excluded by the governing ClinGen PALB2 VCEP Version 1.3 specification, so no PS3 or BS3 strength is assigned.
No other ACMG/AMP criterion was adjudicated.
Within the requested group, only PS4 is applicable under the PALB2 VCEP; PP4, PP5, BP5, and BP6 are explicitly not applicable.
PS4 Strong is met because the exact-variant case-control comparison, supplemented with matched-ancestry gnomAD v4.1 NFE controls, satisfies p≤0.05 and OR≥3 with a lower 95% CI≥1.5.
PM3 was not assessed because the VCEP-specific Fanconi Anemia table contains no entry for this variant and the available reports do not establish the required phenotype and phase.
BP2 is not applicable under the PALB2 VCEP Version 1.3 specification.
Only PP3, BP4, and BP7 were adjudicated under the ClinGen PALB2 VCEP version 1.3 rules.
PP3 was evaluated on the VCEP's splice-prediction path and was not met because SpliceAI maximum delta score 0.006 is below 0.2.
BP4 and BP7 are not applicable because the variant is missense and outside each criterion's VCEP-defined scope.
No criteria match.
Met · 2
PS4StrongVCEPMet: case-control comparison gives OR 86.22 (95% CI 11.87–625.98) and Fisher p=0.0118, satisfying the VCEP thresholds OR ≥3 and p≤0.05.
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Reasoning
The VCEP PS4 rule requires a case-control study with p-value ≤.05 and either an odds ratio ≥3 or lower 95% CI ≥1.5. Blanco et al. (PMID:23935836, Table 2) reported PALB2 c.110G>A in 1 of 132 Spanish hereditary breast/ovarian cancer families (1 alternate allele and 263 reference alleles) and 0 alternate alleles in the reported CEU 1000 Genomes comparison population. Using the matched-ancestry gnomAD v4.1 NFE control frequency as permitted for a case-frequency comparison (52 alternate and 1,179,114 reference alleles), the allele-count OR is 86.22, approximate 95% CI 11.87–625.98, and two-sided Fisher exact p=0.0118. The required comparisons are p=0.0118 ≤ 0.05 (yes), OR=86.22 ≥ 3 (yes), and lower 95% CI=11.87 ≥ 1.5 (yes); therefore PS4 Strong is met. The literature packet's exact-variant case reports were checked: PMID:28319063 reports R37H in 1/132 Spanish families and 1/565 WECARE breast-cancer patients, while PMID:23935836 supplies the case/control comparison; no other reviewed paper provided a stronger variant-specific case-control estimate.
VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥3 **or** lower 95% CI ≥1.5).
Evidence considered
Blanco et al. (PMID:23935836), Table 2: c.110G>A/p.Arg37His occurred in 1 of 132 Spanish breast/ovarian cancer families with pancreatic-cancer cases; genotype counts were 131 AA, 1 AB, 0 BB, corresponding to 1 alternate and 263 reference alleles, while the reported CEU 1000 Genomes comparison had 0% alternate-allele frequency.
Matched-ancestry gnomAD v4.1 NFE control data: 52 alternate alleles among 1,179,166 total alleles, hence 1,179,114 reference alleles; used as the control frequency for the case-frequency comparison.
Foo et al. (PMID:28319063) independently reports R37H in 1/132 Spanish breast/ovarian cancer families and 1/565 unilateral breast cancer patients in the WECARE study, confirming affected-cohort observations but not supplying an unaffected-control comparison for this variant.
PM2VCEPNot met: the highest gnomAD v4.1 subpopulation AF is 0.0000668568, above the VCEP PM2 cutoff of 0.00000333.
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Reasoning
The PALB2 VCEP PM2 rule requires frequency ≤1/300,000 (0.000333%) in the gnomAD subpopulation with the highest frequency, with a single-observation exception only when the variant is absent from every other subpopulation. The all-comers gnomAD highest-subpopulation frequencies exceed the threshold: East Asian AF 0.000150361 (0.01504%) in v2.1 and 0.0000668568 (0.00669%) in v4.1. Each has multiple observed alleles, so the single-observation exception does not apply. The VCEP does not specify a non-cancer-only source for PM2, so the all-comers entries are used.
VCEP rule
Frequency ≤ 1/300,000 (**0.000333%**) in gnomAD subpopulation with the highest frequency ... Exception: If >0.000333% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2\_supporting would apply.
Evidence considered
gnomAD v2.1 all-comers: highest subpopulation is East Asian, AF = 0.000150361 (0.01504%), 3/19,952 alleles, homozygotes = 0.
gnomAD v4.1 all-comers: highest subpopulation is East Asian, AF = 0.0000668568 (0.00669%), 3/44,872 alleles, homozygotes = 0.
Both all-comers datasets have more than one observed allele, so the VCEP single-observation exception does not apply.
No VCEP instruction specifies a non-cancer-only population source for PM2; therefore the all-comers gnomAD entries were used.
PP3VCEPNot met: SpliceAI maximum delta score is 0.006, below the PALB2 VCEP PP3 threshold of ≥0.2 for predicted splice impact.
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Reasoning
The PALB2 VCEP limits PP3 to splice prediction evidence for silent, missense/in-frame, and specified intronic variants, requiring predicted splicing impact by SpliceAI at a maximum delta score of at least 0.2; the missense-prediction path is explicitly not used. NM_024675.4:c.110G>A is a missense variant, and its SpliceAI maximum delta score is 0.006, below the VCEP threshold, so PP3 is not met.
VCEP rule
* Missense: Do not use.
* Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
PALB2 VCEP PP3 rule: splice prediction is applicable to missense/in-frame variants and requires SpliceAI ≥0.2; the missense-prediction path is not used.
SpliceAI Lookup for NM_024675.4:c.110G>A: DS_AG 0.006, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002; maximum delta score 0.006.
Case normalization identifies NM_024675.4:c.110G>A as NP_078951.2:p.(Arg37His), a missense variant.
BA1VCEPNot met: gnomAD v4.1 grpmax FAF is 0.003424%, below the VCEP BA1 threshold of >0.1%.
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Reasoning
The PALB2 VCEP BA1 rule requires grpmax filtering allele frequency >0.1% in gnomAD. The applicable all-comers gnomAD values are below this threshold: gnomAD v2.1 grpmax FAF 0.004412% (4.412e-05) and gnomAD v4.1 grpmax FAF 0.003424% (3.424e-05). The VCEP does not specify a non-cancer-only source for BA1, so the all-comers values are used.
BS1VCEPNot met: gnomAD v2.1 grpmax FAF is 0.004412%, below the VCEP BS1 threshold of >0.01%.
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Reasoning
The PALB2 VCEP BS1 rule requires grpmax filtering allele frequency >0.01% in gnomAD. The applicable all-comers gnomAD values exceed this threshold: gnomAD v2.1 grpmax FAF 0.004412% does not exceed it, while gnomAD v4.1 grpmax FAF 0.003424% also does not exceed it. Therefore BS1 is not met.
PM3VCEPNot assessed: no Fanconi Anemia PM3-table entry or confirmed pathogenic variant in trans was available for c.110G>A, p.Arg37His, or p.R37H.
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Reasoning
The PALB2 VCEP PM3 rule requires a recessive-disease observation detected in trans with a pathogenic variant and assigns points from the Fanconi Anemia PM3 table. The governing file PALB2_PM3_BS2_1.3.pdf was searched for c.110G>A, p.Arg37His, and p.R37H, with no matching entry. The available variant-specific literature reports the variant in a Spanish cancer-family cohort and in an independent breast-cancer study, but does not establish Fanconi Anemia phenotype, a pathogenic variant in trans, or phase. Therefore, PM3 cannot be evaluated from the available evidence and no PM3 strength is assigned.
VCEP rule
For recessive disorders, detected in trans with a pathogenic variant ... Points per unrelated PALB2-related (FANCN) Fanconi Anemia Proband (PM3) ... Phenotype consistent with PALB2-related FA ... 2.0 ... 1.0
Evidence considered
PALB2_PM3_BS2_1.3.pdf, PM3 section: the rule is for recessive disorders with the variant detected in trans with a pathogenic variant; its Fanconi Anemia table assigns 2.0 points per unrelated proband when the phenotype is consistent with PALB2-related Fanconi Anemia and the other variant is confirmed in trans or the assessed variant is homozygous, versus 1.0 point when phase is unknown.
PALB2_PM3_BS2_1.3.pdf searched for c.110G>A, p.Arg37His, and p.R37H: no matching variant entry was found.
PMID:23935836 reports c.110G>A (p.Arg37His) once in a Spanish breast/ovarian cancer-family cohort, but provides no Fanconi Anemia phenotype or phase-resolved pathogenic variant in trans.
PMID:28319063 reports p.R37H in two breast-cancer studies and functional assays, but provides no Fanconi Anemia phenotype or phase-resolved pathogenic variant in trans.
Still missing
No entry for c.110G>A, p.Arg37His, or p.R37H was found in PALB2_PM3_BS2_1.3.pdf; a Fanconi Anemia phenotype and phase-resolved pathogenic variant in trans remain undocumented.
PP1VCEPNot assessed: one family occurrence is reported, but no affected-relative count, meioses, LOD, or Bayes factor is available for the VCEP thresholds.
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Reasoning
The VCEP permits PP1 for autosomal-dominant segregation at Supporting when LOD ≥0.3 or Bayes Factor (LR) ≥2:1, Moderate when LOD ≥.60 or Bayes Factor (LR) ≥4:1, and Strong when LOD ≥1.26 or Bayes Factor (LR) ≥18:1. The available variant-specific report describes one occurrence of c.110G>A/p.Arg37His in 1 of 132 Spanish breast/ovarian cancer families, but provides no affected-relative segregation count, meioses, LOD, or Bayes factor, so no PP1 strength can be assigned.
VCEP rule
* AD Condition: LOD ≥1.26 or Bayes Factor (LR) ≥18:1
* AR Condition: Segregation in ≥3 affected relatives
* AD Condition: LOD ≥.60 or Bayes Factor (LR) ≥4:1
* AR Condition: Segregation in 2 affected relatives
* AD Condition: LOD ≥0.3 or Bayes Factor (LR) ≥2:1
* AR Condition: Segregation in 1 affected relative
Evidence considered
PALB2 VCEP CSPEC PP1 rule: AD Supporting requires LOD ≥0.3 or Bayes Factor (LR) ≥2:1; AD Moderate requires LOD ≥.60 or Bayes Factor (LR) ≥4:1; AD Strong requires LOD ≥1.26 or Bayes Factor (LR) ≥18:1.
Blanco et al. 2013, PMID:23935836, Results paragraph describing the 21 additional PALB2 variants and Table 2: PALB2 c.110G>A (p.Arg37His) was observed once among 132 Spanish BRCA1/BRCA2-negative breast/ovarian cancer families with personal or family pancreatic cancer history; the report does not provide affected-relative segregation, meioses, LOD, or Bayes factor for this variant.
Still missing
Affected-relative segregation count and phase information are not reported.
BS2VCEPNot assessed: the only exact-variant cohort report is an affected cancer-family observation, not qualifying healthy-adult BS2 evidence.
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Reasoning
The PALB2 VCEP BS2 rule requires qualifying healthy-adult observations in clinical or research cohorts, excludes population cohorts such as gnomAD, and assigns strength from the Fanconi Anemia BS2 point tables. The available exact-variant literature observation is one heterozygous carrier in an affected Spanish breast/ovarian cancer family cohort, not a healthy adult observation. No qualifying BS2 points can therefore be assigned. The governing VCEP table file was searched for c.110G>A, p.Arg37His, and p.R37H; no variant-specific entry was found.
VCEP rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. ... Do not use for individuals in population based cohorts, such as gnomAD. ... VUA should not be bioinformatically predicted (or experimentally proven) to have a clinically important effect on protein or mRNA splicing. ... BS2 **≥ 4** points
See Fanconi Anemia BS2 tables for approach to assign points per proband.
Evidence considered
PALB2_PM3_BS2_1.3.pdf, BS2 section: healthy-adult observations are required; population cohorts such as gnomAD must not be used; BS2 strength is assigned from the Fanconi Anemia BS2 point table.
PALB2_PM3_BS2_1.3.pdf, BS2 table: points apply to probands meeting age/cancer diagnosis criteria and to phenotyped clinical or research cohorts, not frequency-based population data.
PMID:23935836 reports c.110G>A (p.Arg37His) once in a Spanish hereditary breast/ovarian cancer family cohort; this is an affected cancer cohort observation and does not establish the healthy-adult BS2 condition.
The VCEP file was searched for c.110G>A, p.Arg37His, and p.R37H; no matching variant-specific table entry was found.
Still missing
No qualifying healthy-adult clinical or research cohort observation was available for BS2.
No entry for c.110G>A, p.Arg37His, or p.R37H was found in PALB2_PM3_BS2_1.3.pdf.txt.
BS4VCEPNot assessed: the report lacks informative non-segregating relatives and provides no LOD or Bayes factor to meet any BS4 threshold.
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Reasoning
The VCEP defines BS4 from non-segregation using LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1 for Strong, LOD ≤ -.64 or Bayes Factor (LR) ≤.23 for Moderate, and LOD ≤-.32 or Bayes Factor (LR) ≤.48 for Supporting. The available variant-specific report identifies one family occurrence but provides no informative unaffected-relative testing, non-segregation count, LOD, or Bayes factor; absence of reported segregation is not sufficient to establish BS4.
VCEP rule
LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1 ... LOD ≤ -.64 or Bayes Factor (LR) ≤.23 ... LOD ≤-.32 or Bayes Factor (LR) ≤.48
Blanco et al. 2013, PMID:23935836, Results paragraph describing the 21 additional PALB2 variants and Table 2: c.110G>A/p.Arg37His was observed once in the family cohort, but the report does not provide informative unaffected-relative testing, non-segregation observations, LOD, or Bayes factor.
Still missing
Informative unaffected-relative testing and non-segregation observations are not reported.
No non-segregation LOD or Bayes factor is available.
Not applicable · 18· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.110G>A is a missense p.Arg37His variant, whereas the PALB2 PVS1 rule applies to specified null-variant classes.
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Reasoning
PVS1 is not applicable. The case identifies NM_024675.4:c.110G>A as the missense variant NP_078951.2:p.(Arg37His) (p.R37H) in exon 3, not a nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, or exon-deletion variant. The PALB2 PVS1 guide defines PVS1 for null variants of those types in a gene where loss of function is a known disease mechanism; therefore the PVS1 decision tree, NMD assessment, and truncation-strength tiers do not apply. The governing PALB2_PVS1_v1.3.pdf.txt was searched for c.110G>A, p.Arg37His, and p.R37H, and no variant-specific table entry was found.
VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease
Evidence considered
Case consequence: NM_024675.4:c.110G>A produces NP_078951.2:p.(Arg37His) (p.R37H), classified as missense in exon 3.
The governing PALB2 PVS1 guide was searched under c.110G>A, p.Arg37His, and p.R37H; no matching variant-specific row or pre-assigned PVS1 code was found.
The VCEP PVS1 rule is restricted to null variants: nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, or single/multi-exon deletion in a gene where loss of function is a known mechanism of disease.
Still missing
No variant-specific entry for c.110G>A, p.Arg37His, or p.R37H was found in PALB2_PVS1_v1.3.pdf.txt.
PS1N/ANot applicable: PALB2's PS1 rule excludes missense changes because missense disease mechanism is not yet confirmed.
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Reasoning
The variant is missense (p.Arg37His; p.R37H), and the PALB2 PS1 specification states that missense changes must not use PS1 because missense changes are not yet confirmed as a disease mechanism. The governing PS1 file contains no exact entry for c.110G>A, p.Arg37His, or p.R37H.
VCEP rule
Missense: Do not use. Missense changes are not yet confirmed as a mechanism of disease for PALB2.
Evidence considered
Case normalization identifies NM_024675.4:c.110G>A as the missense substitution p.(Arg37His), also written p.(R37H).
PALB2_PS1_1.3.pdf, PS1 rule: the missense route is explicitly excluded; its splicing table is therefore not applicable to this missense variant.
The required exact-notation searches found no c.110G>A, p.Arg37His, or p.R37H entry in PALB2_PS1_1.3.pdf.txt.
Still missing
No exact c.110G>A, p.Arg37His, or p.R37H entry was found in PALB2_PS1_1.3.pdf.txt; this is not evidence that the underlying evidence is absent.
PS3VCEPNot applicable: the PALB2 VCEP Version 1.3 explicitly designates PS3 as not applicable for this framework.
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Reasoning
PS3 is not applicable under the ClinGen PALB2 VCEP Version 1.3 specification. The VCEP criteria entry explicitly marks PS3 as not applicable; therefore, functional assay evidence, including any variant-specific protein assay, cannot be assigned as PS3 under this governing framework.
VCEP rule
For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion).
Evidence considered
ClinGen PALB2 VCEP Version 1.3 CSPEC PS3 entry: applicability = "Not applicable"; instructions state, "For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion)."
PM1VCEPNot applicable: the PALB2 VCEP excludes PM1 because missense pathogenic variation is not yet confirmed as a disease mechanism.
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Reasoning
The PALB2 VCEP marks PM1 not applicable and states that missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease. The case's vcep_materials.json domain_tables key is empty, so no authoritative domain entry overrides this VCEP applicability decision.
VCEP rule
Do not use: Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.
Evidence considered
The PALB2 CSPEC entry for PM1 is marked Not applicable and instructs: Do not use because missense pathogenic variation in PALB2 is not yet confirmed as a disease mechanism.
vcep_materials.json contains no domain_tables entry for PALB2; therefore no authoritative complete domain list applies to this criterion.
PM4VCEPNot applicable: the PALB2 VCEP CSPEC entry explicitly marks PM4 as Not Applicable for this framework.
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Reasoning
PM4 is not applicable under the PALB2 VCEP specification. The consolidated CSPEC entry for PM4 explicitly marks the criterion as Not Applicable, so no independent protein-length-change or repeat-region assessment may replace that governing applicability decision.
VCEP rule
Not Applicable
Evidence considered
PALB2 VCEP CSPEC criterion entry: PM4, applicability = Not Applicable.
PM5N/ANot applicable: PM5 Supporting is limited to truncating variants upstream of p.His1184 and excludes missense changes.
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Reasoning
The PALB2 VCEP limits PM5 Supporting to NMD-prone truncating variants with premature termination codons upstream of p.His1184, and explicitly states not to use PM5 for missense changes. This variant is missense p.Arg37His.
VCEP rule
* DNA Variants: Apply to all NMD-prone, truncating variants receiving PVS1 (must be at VeryStrong) with premature termination codons upstream of p.His1184
* Splice Variants: Apply to all observed (not predicted) NMD-prone, truncating variants receiving PVS1(RNA) (must be at VeryStrong with high-quality RNA data) with premature termination codons upstream of p.His1184. This is not applicable for predicted splice impact without RNA data or PVS1(RNA) at reduced strength.
Evidence considered
The PALB2 CSPEC PM5 rule defines PM5 Supporting for NMD-prone truncating variants with premature termination codons upstream of p.His1184 and explicitly excludes missense changes.
The case variant is the missense substitution p.Arg37His (p.R37H), so same-residue missense comparator evidence cannot activate this VCEP PM5 rule.
PP2VCEPNot applicable: the PALB2 VCEP excludes PP2 because missense is not yet confirmed or refuted as a disease mechanism.
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Reasoning
The PALB2 VCEP marks PP2 not applicable and instructs not to use it because missense is not yet confirmed or refuted as a mechanism of disease for PALB2. The variant is missense p.Arg37His.
VCEP rule
Do not use. Missense is not yet confirmed or refuted as a mechanism of disease for PALB2
Evidence considered
The PALB2 CSPEC entry for PP2 is marked Not applicable and explicitly says not to use PP2 because missense is not yet confirmed or refuted as a mechanism of disease.
The case variant is a missense substitution, p.Arg37His (p.R37H).
PP4VCEPNot applicable: the VCEP excludes PP4 for dominant PALB2 cancer because breast-cancer features cannot distinguish hereditary from sporadic disease.
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Reasoning
The PALB2 VCEP marks PP4 not applicable for autosomal dominant disease because breast cancer is genetically heterogeneous and features cannot readily distinguish hereditary from sporadic causes. This variant is being evaluated in the PALB2-related cancer-predisposition context, so PP4 cannot be applied.
VCEP rule
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.
Evidence considered
The VCEP instruction for PP4 states that it should not be used for autosomal dominant disease because breast cancer has multiple genetic etiologies and no readily distinguishing features.
PP5VCEPNot applicable: the PALB2 VCEP explicitly recommends that PP5 not be used for this variant or any case.
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Reasoning
The PALB2 VCEP marks PP5 not applicable and explicitly recommends that this criterion not be used; therefore reported pathogenic classifications or literature assertions cannot establish PP5 in this case.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
The VCEP PP5 instruction states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BS3VCEPNot applicable: the PALB2 VCEP Version 1.3 explicitly designates BS3 as not applicable for this framework.
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Reasoning
BS3 is not applicable under the ClinGen PALB2 VCEP Version 1.3 specification. The VCEP criteria entry explicitly marks BS3 as not applicable; therefore, functional assay evidence showing no damaging effect cannot be assigned as BS3 under this governing framework.
VCEP rule
For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion).
Evidence considered
ClinGen PALB2 VCEP Version 1.3 CSPEC BS3 entry: applicability = "Not applicable"; instructions state, "For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion)."
BP2VCEPNot applicable: the ClinGen PALB2 VCEP Version 1.3 explicitly marks BP2 as not applicable.
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Reasoning
BP2 is explicitly marked not applicable in the ClinGen PALB2 VCEP Version 1.3 criteria entry. The generic BP2 concept of allelic observations therefore cannot be assigned under this governing framework, regardless of the available literature or phase information.
VCEP rule
Use ATM PM3/BP2 table.
Evidence considered
ClinGen PALB2 VCEP Version 1.3 CSPEC BP2 entry: applicability = "Not applicable"; the entry lists the original BP2 concept but provides no applicable strength rule.
BP3VCEPNot applicable: the PALB2 VCEP CSPEC entry explicitly marks BP3 as Not Applicable for this framework.
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Reasoning
BP3 is not applicable under the PALB2 VCEP specification. The consolidated CSPEC entry for BP3 explicitly marks the criterion as Not Applicable, so no repeat-region or in-frame-deletion rule may be substituted from generic ACMG/AMP guidance.
VCEP rule
Not Applicable
Evidence considered
PALB2 VCEP CSPEC criterion entry: BP3, applicability = Not Applicable.
BP4N/ANot applicable: the PALB2 VCEP excludes missense variants from BP4, and c.110G>A produces the missense change p.Arg37His.
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Reasoning
The PALB2 VCEP states that BP4 is not used for missense variants. NM_024675.4:c.110G>A produces p.(Arg37His) and is therefore outside BP4 scope, regardless of its low SpliceAI score.
VCEP rule
* Missense: Do not use.
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
PALB2 VCEP BP4 rule: the missense path is not used and the splicing path explicitly says not to apply BP4 for missense variants.
Case normalization identifies NM_024675.4:c.110G>A as NP_078951.2:p.(Arg37His), a missense variant.
BP5VCEPNot applicable: the VCEP excludes BP5 because PALB2 moderate penetrance and multiple pathogenic variants make alternate molecular-basis evidence unreliable.
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Reasoning
The PALB2 VCEP marks BP5 not applicable and instructs users not to apply it because multiple pathogenic variants can occur without a noticeable phenotype difference and PALB2 has moderate penetrance.
VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, PALB2 has moderate penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
The VCEP BP5 instruction states: do not use, because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference and PALB2 has moderate penetrance.
BP6VCEPNot applicable: the PALB2 VCEP explicitly recommends that BP6 not be used for this variant or any case.
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Reasoning
The PALB2 VCEP marks BP6 not applicable and explicitly recommends that this criterion not be used; reputable benign assertions therefore cannot establish BP6 under this governing framework.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
The VCEP BP6 instruction states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7N/ANot applicable: BP7 is limited to synonymous or deep intronic variants, whereas c.110G>A is the missense variant p.Arg37His.
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Reasoning
The PALB2 VCEP limits BP7 to synonymous substitutions and deep intronic variants, with a separate RNA path for silent substitutions and intronic variants. NM_024675.4:c.110G>A is a missense variant, so it lies outside BP7 scope.
VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively.
* BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
PALB2 VCEP BP7 rule: BP7 applies to synonymous and defined deep intronic variants; BP7(RNA) applies to silent substitutions and intronic variants.
Case normalization identifies NM_024675.4:c.110G>A as NP_078951.2:p.(Arg37His), a missense variant.
AF 3.9e-05 · 63 / 1,613,090 alleles · 0 hom · FAF 3.4e-05
East Asian3 / 44,872
6.7e-05
Remaining individuals3 / 62,480
4.8e-05
European (non-Finnish)52 / 1,179,166
4.4e-05
African/African American2 / 74,962
2.7e-05
South Asian2 / 91,052
2.2e-05
Admixed American1 / 59,998
1.7e-05
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 3.9e-05 · 11 / 282,840 alleles · 0 hom · FAF 4.4e-05
East Asian3 / 19,952
0.00015
South Asian2 / 30,612
6.5e-05
African/African American1 / 24,958
4e-05
European (non-Finnish)5 / 129,174
3.9e-05
0 alternate alleles recorded in 4 other groups: Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.90555e-05; MAF= 0.00391%, 63/1613090 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.68568e-05; MAF= 0.00669%, 3/44872 alleles, homozygotes = 0); grpmax FAF= 3.424e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88912e-05; MAF= 0.00389%, 11/282840 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000150361; MAF= 0.01504%, 3/19952 alleles, homozygotes = 0); grpmax FAF= 4.412e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -10 bp
0.002
SpliceAI acceptor gainat +37 bp
0.006
SpliceAI donor lossat -101 bp
0.002
SpliceAI donor gainat +119 bp
0.000
Pangolin splice lossmagnitude shown
-0.012
Pangolin splice gain
0.002
Other predictors
REVEL
0.158
BayesDel
-0.123
How the predictions were used
PP3VCEPNot met: SpliceAI maximum delta score is 0.006, below the PALB2 VCEP PP3 threshold of ≥0.2 for predicted splice impact.
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Reasoning
The PALB2 VCEP limits PP3 to splice prediction evidence for silent, missense/in-frame, and specified intronic variants, requiring predicted splicing impact by SpliceAI at a maximum delta score of at least 0.2; the missense-prediction path is explicitly not used. NM_024675.4:c.110G>A is a missense variant, and its SpliceAI maximum delta score is 0.006, below the VCEP threshold, so PP3 is not met.
VCEP rule
* Missense: Do not use.
* Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
PALB2 VCEP PP3 rule: splice prediction is applicable to missense/in-frame variants and requires SpliceAI ≥0.2; the missense-prediction path is not used.
SpliceAI Lookup for NM_024675.4:c.110G>A: DS_AG 0.006, DS_AL 0.002, DS_DG 0.000, DS_DL 0.002; maximum delta score 0.006.
Case normalization identifies NM_024675.4:c.110G>A as NP_078951.2:p.(Arg37His), a missense variant.
BP4N/ANot applicable: the PALB2 VCEP excludes missense variants from BP4, and c.110G>A produces the missense change p.Arg37His.
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Reasoning
The PALB2 VCEP states that BP4 is not used for missense variants. NM_024675.4:c.110G>A produces p.(Arg37His) and is therefore outside BP4 scope, regardless of its low SpliceAI score.
VCEP rule
* Missense: Do not use.
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**). Do not apply for missense variants.
Evidence considered
PALB2 VCEP BP4 rule: the missense path is not used and the splicing path explicitly says not to apply BP4 for missense variants.
Case normalization identifies NM_024675.4:c.110G>A as NP_078951.2:p.(Arg37His), a missense variant.
BP7N/ANot applicable: BP7 is limited to synonymous or deep intronic variants, whereas c.110G>A is the missense variant p.Arg37His.
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Reasoning
The PALB2 VCEP limits BP7 to synonymous substitutions and deep intronic variants, with a separate RNA path for silent substitutions and intronic variants. NM_024675.4:c.110G>A is a missense variant, so it lies outside BP7 scope.
VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively.
* BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
PALB2 VCEP BP7 rule: BP7 applies to synonymous and defined deep intronic variants; BP7(RNA) applies to silent substitutions and intronic variants.
Case normalization identifies NM_024675.4:c.110G>A as NP_078951.2:p.(Arg37His), a missense variant.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.158. BayesDel score = -0.122921.
8 paper records listed. 2 cited in the classification.
Cited in the classification
Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases.
Blanco A et al. · 2013
The paper explicitly reports PALB2 c.110G>A (NP_078951.2:p.Arg37His; p.(R37H)) once among 132 BRCA1/BRCA2-negative Spanish breast/ovarian cancer families with personal or family pancreatic cancer history. It provides no affected-relative segregation, informative unaffected-relative non-segregation, meioses, LOD, or Bayes factor for this variant.
For the missense variant c.110 G.A (p.Arg37His) two of the three prediction programs considered the variant as deleterious
Location Results, paragraph describing the 21 additional PALB2 variants; Table 2; Discussion, final paragraph before Conclusions
Context Direct sequencing of all PALB2 coding exons and intron/exon boundaries, MLPA, in 132 BRCA1/BRCA2-negative Spanish breast/ovarian cancer families with personal or family pancreatic cancer history; variant-level cDNA analysis was also reported for the carrier.
Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.
Foo TK et al. · 2017 Jul 20
The paper explicitly studied PALB2 c.110G>A (p.R37H), identifying it as one of five germline N-terminal coiled-coil VUSs reported in two independent studies: 1/132 non-BRCA1/BRCA2 Spanish breast/ovarian cancer families with at least one pancreatic cancer case and 1/565 unilateral breast cancer patients in the WECARE study. These are affected cohorts and do not provide an unaffected-control comparison for R37H.
K18R and R37H also reduced PALB2 HR activity, suggesting that the variants may affect the integrity of the coiled-coil motif
Location Results, “VUSs in the coiled-coil motif of PALB2”; Table 1; Discussion
Context Germline variant reports in two independent affected cohorts, including 1/132 Spanish families and 1/565 WECARE breast-cancer patients; functional PALB2 interaction and homologous-recombination assays.
Other recorded publications
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.
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= 3.90555e-05; MAF= 0.00391%, 63/1613090 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.68568e-05; MAF= 0.00669%, 3/44872 alleles, homozygotes = 0); grpmax FAF= 3.424e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88912e-05; MAF= 0.00389%, 11/282840 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000150361; MAF= 0.01504%, 3/19952 alleles, homozygotes = 0); grpmax FAF= 4.412e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 126590)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.158. BayesDel score = -0.122921.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55166817, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.