LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-18
Case ID: NM_024675.4_c.2135C_T_20261018_025407
Framework: ACMG/AMP 2015
Variant classification summary

NM_024675.4:c.2135C>T

PALB2  · NP_078951.2:p.(Ala712Val)  · NM_024675.4
GRCh37: chr16:23641340 G>A  ·  GRCh38: chr16:23630019 G>A
Gene: PALB2 Transcript: NM_024675.4
Final call
Benign
BA1 stand-alone benign BS1 strong BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PALB2
Transcript
NM_024675.4
Protein
NP_078951.2:p.(Ala712Val)
gnomAD AF
0.00019515446940907228 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Benign: BA1 is met because the gnomAD grpmax filtering frequency is 0.412487%, above the >0.1% threshold.
2
Benign: BS1 is met at strong strength because the gnomAD grpmax filtering frequency is 0.412487%, above the >0.01% threshold.
3
Benign: BP1 is met at supporting strength because c.2135C>T is a missense substitution.
Final determination: PALB2 VCEP Rule17 is satisfied by one adjudicated Benign.Stand Alone criterion, BA1, so the final classification is Benign.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: c.2135C>T produces the missense substitution p.Ala712Val, outside the PALB2 VCEP PVS1 null-variant scope.
cspec pvs1_variant_assessment vcep_palb2_pvs1_v1_3 PMID:20589654
PS1 N/A Not applicable: PALB2 VCEP PS1 excludes missense changes, and the PS1 table has no c.2135C>T, p.Ala712Val, or p.A712V entry.
cspec vcep_palb2_ps1_1_3
PS2 N/A Not applicable: the PALB2 VCEP explicitly designates PS2 as not applicable.
cspec
PS3 N/A Not applicable: the PALB2 VCEP version 1.3 explicitly marks PS3 as not applicable, so no pathogenic functional-evidence strength is assigned.
cspec
PS4 Not assessed Not assessed: the variant was reported in one cohort, but no VCEP-required case-control p-value, effect estimate, or confidence interval is available.
cspec PMID:20589654 PMID:22241545
PM1 N/A Not applicable: the PALB2 VCEP CSPEC explicitly marks PM1 as Not Applicable for this framework.
cspec
PM2 Not met Not met: the highest gnomAD v4.1 subpopulation AF is 0.560871%, above the VCEP PM2 threshold of 0.000333%.
cspec gnomad_v4
PM3 Not assessed Not assessed: the exact variant lacks documented Fanconi Anemia phenotype, pathogenic variant in trans, homozygosity, or phase information required by the VCEP PM3 table.
vcep_palb2_pm3_bs2_1_3 PMID:20589654
PM4 N/A Not applicable: the PALB2 VCEP explicitly marks PM4 Not Applicable, and this variant is a protein-preserving missense SNV.
cspec pvs1_variant_assessment
PM5 N/A Not applicable: PM5 is limited to NMD-prone truncating variants with PVS1 VeryStrong, whereas p.Ala712Val is missense.
cspec
PM6 N/A Not applicable: the PALB2 VCEP explicitly designates PM6 as not applicable.
cspec
PP1 Not assessed Not assessed: the exact-variant report provides one proband but no affected relatives, parental testing, segregation count, LOD, or LR threshold value.
cspec PMID:20589654
PP2 N/A Not applicable: the PALB2 VCEP CSPEC explicitly marks PP2 as Not Applicable.
cspec
PP3 Not met Not met: SpliceAI maximum delta score 0.028 is below the VCEP PP3 threshold of ≥0.2 for predicted splice impact.
cspec spliceai
PP4 N/A Not applicable: the VCEP excludes PP4 for dominant PALB2 cancer predisposition because breast-cancer phenotypes are not sufficiently specific.
cspec
PP5 N/A Not applicable: the PALB2 VCEP explicitly prohibits PP5, regardless of available external pathogenicity assertions.
cspec
BA1 Met Met: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BA1 threshold of >0.1%.
cspec gnomad_v4
BS1 Met Met: gnomAD v4.1 grpmax FAF is 0.412487%, exceeding the PALB2 VCEP BS1 threshold of >0.01%.
cspec gnomad_v4
BS2 Not assessed Not assessed: gnomAD reports homozygotes, but no Fanconi Anemia BS2 table points can be assigned without proband phenotype and age data.
cspec vcep_palb2_pm3_bs2_1_3 gnomad_v4
BS3 N/A Not applicable: the PALB2 VCEP version 1.3 explicitly marks BS3 as not applicable, so no benign functional-evidence strength is assigned.
cspec
BS4 Not assessed Not assessed: no non-segregating relatives, informative meioses, LOD, or LR are reported for comparison with the VCEP BS4 thresholds.
cspec
BP1 Met Met, Supporting: BP1 applies to all missense variants, and NM_024675.4:c.2135C>T encodes missense p.Ala712Val.
cspec
BP2 N/A Not applicable: the PALB2 Version 1.3 VCEP explicitly marks BP2 as Not Applicable.
cspec
BP3 N/A Not applicable: the PALB2 VCEP explicitly marks BP3 Not Applicable, and c.2135C>T is a missense SNV.
cspec pvs1_variant_assessment
BP4 N/A Not applicable: the VCEP BP4 rule excludes missense variants, including its splice-prediction path.
cspec
BP5 N/A Not applicable: the PALB2 VCEP prohibits BP5 because co-occurring pathogenic variants do not reliably distinguish the phenotype in moderate-penetrance PALB2 disease.
cspec
BP6 N/A Not applicable: the PALB2 VCEP explicitly prohibits BP6, regardless of available external benign or likely-benign reports.
cspec
BP7 N/A Not applicable: BP7 is limited by the VCEP to synonymous or deep intronic variants, not this missense substitution.
cspec
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