PALB2 c.2673C>T, p.Cys891=
NM_024675.4:c.2673C>T
COSMIC ID: COSM3279833
Likely Benign
This synonymous PALB2 variant (c.2673C>T; p.C891=) is classified as Likely Benign based on two supporting benign criteria (BP4, BP6) with no evidence meeting pathogenic criteria.
ACMG/AMP Criteria Applied
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
PALB2
Transcript
NM_024675.4
MANE Select
Total Exons
13
Strand
Reverse (−)
Reference Sequence
NC_000016.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_024675.3 | RefSeq Select | 13 exons | Reverse |
Variant Details
HGVS Notation
NM_024675.4:c.2673C>T
Protein Change
C891=
Location
Exon 7
(Exon 7 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM3279833
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.2673C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00239%
Rare
Highest in Population
East Asian
0.0163%
Low Frequency
Global: 0.00239%
East Asian: 0.0163%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251486Alt: 6Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00239%, 6/251486 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.0163%, 3/18394 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Likely Benign
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
7 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.69
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific; very strong strength for null variants." The evidence for this variant shows: it is a synonymous (p.C891=) change not predicted to impact splicing. Therefore, this criterion is not applied because the variant is not a null (loss-of-function) allele.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP PS1 guidelines, the rule for PS1 is: "Use PALB2 PS1 Splicing table; strong for same amino acid change via different nucleotide when pathogenic." The evidence for this variant shows: no known pathogenic variant alters the same codon to the same amino acid, and this is a synonymous change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies have been reported. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP PS4 guidelines, the rule for PS4 is: "Strong if case-control studies with significant odds ratio/hazard ratio ≥3 (lower 95% CI ≥1.5)." The evidence for this variant shows: no case-control or family segregation data. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: it is a synonymous change outside known functional domains. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting if variant absent in gnomAD or present in ≤1/300,000 alleles." The evidence for this variant shows: MAF=0.00239% (6/251,486 alleles), which exceeds the ≤1/300,000 (0.00033%) threshold. Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP PM3 guidelines, the rule for PM3 is: "Use Fanconi Anemia PM3 tables for recessive in trans observations." The evidence for this variant shows: no compound heterozygous or homozygous observations in affected individuals consistent with recessive inheritance. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame indels or stop-loss variants." The evidence for this variant shows: it is a synonymous substitution with no length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP PM5 guidelines, the rule for PM5 is: "Supporting for frameshifting or truncating variants upstream of p.Tyr1183." The evidence for this variant shows: it is synonymous, not truncating. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo (without confirmation of paternity and maternity)." The evidence for this variant shows: no de novo information. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP PP1 guidelines, the rule for PP1 is: "Supporting/Moderate/Strong based on segregation LOD scores in familial cases." The evidence for this variant shows: no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and in which missense are a common mechanism of disease." The evidence for this variant shows: it is synonymous, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP PP3 guidelines, the rule for PP3 is: "Supporting RNA: at least one predictor (e.g. SpliceAI) shows impact on splicing." The evidence for this variant shows: SpliceAI score=0.06 indicating no splice impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype data provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic but evidence not available for independent evaluation." The evidence for this variant shows: ClinVar reports benign/likely benign. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP BA1 guidelines, the rule for BA1 is: "Stand alone if allele frequency >0.1%." The evidence for this variant shows: MAF=0.00239%, which is below 0.1%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP BS1 guidelines, the rule for BS1 is: "Strong if filtering AF >0.01%." The evidence for this variant shows: MAF=0.00239% (0.0000239 fraction), which is below 0.01%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP BS2 guidelines, the rule for BS2 is: "Use Fanconi Anemia BS2 tables for observations in healthy adults." The evidence for this variant shows: no such observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect." The evidence for this variant shows: no functional data. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP BS4 guidelines, the rule for BS4 is: "Strong/Moderate/Supporting segregation data showing lack of cosegregation." The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP BP1 guidelines, the rule for BP1 is: "Supporting for missense variants in genes where only LoF causes disease." The evidence for this variant shows: it is synonymous. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant." The evidence for this variant shows: no such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without known function." The evidence for this variant shows: it is a single-nucleotide change, not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP BP4 guidelines, the rule for BP4 is: "Supporting if RNA: at least one well-established predictor (e.g. SpliceAI) shows no impact on splicing." The evidence for this variant shows: SpliceAI maximum score=0.06, indicating no splicing impact. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such case data. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence is not available for independent evaluation." The evidence for this variant shows: ClinVar entries from eight laboratories report the variant as benign/likely benign without primary evidence. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP BP7 guidelines, the rule for BP7 is: "Supporting for synonymous variants with observed lack of aberrant RNA defect." The evidence for this variant shows: no RNA assay data, only in silico predictions. Therefore, BP7 is not applied.