PALB2 p.Leu1074Val
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is . The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
Uncertain significance
The NM_024675.4(PALB2):c.3220C>G(p.Leu1074Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1074R) has been classified as Uncertain significance. The gene PALB2 is included in the ClinGen Criteria Specification Registry.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
PALB2
NM_024675.4 missense
NM_024675.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 1.97
Publications
2 publications found
Genes affected
PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]
PALB2 Gene-Disease associations (from GenCC):
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- PALB2-related cancer predispositionInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- Fanconi anemia complementation group NInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- pancreatic cancer, susceptibility to, 3Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
new If you want to explore the variant's impact on the transcript NM_024675.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
ACMG classification
Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 38 uncertain in NM_024675.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (REVEL=0.061).
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PALB2 | MANE Select | c.3220C>G | p.Leu1074Val | missense | Exon 12 of 13 | NP_078951.2 | |||
| PALB2 | c.3160C>G | p.Leu1054Val | missense | Exon 11 of 12 | NP_001394225.1 | ||||
| PALB2 | c.3148C>G | p.Leu1050Val | missense | Exon 11 of 12 | NP_001394226.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PALB2 | TSL:1 MANE Select | c.3220C>G | p.Leu1074Val | missense | Exon 12 of 13 | ENSP00000261584.4 | Q86YC2 | ||
| PALB2 | TSL:1 | c.2335C>G | p.Leu779Val | missense | Exon 12 of 13 | ENSP00000454703.2 | H3BN63 | ||
| PALB2 | TSL:5 | c.3226C>G | p.Leu1076Val | missense | Exon 12 of 13 | ENSP00000460666.3 | A0AA52I2C1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461732Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727194 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1461732
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727194
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39696
South Asian (SAS)
AF:
AC:
0
AN:
86246
European-Finnish (FIN)
AF:
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111874
Other (OTH)
AF:
AC:
0
AN:
60394
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
31
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
-
3
-
not provided (3)
-
1
-
Familial cancer of breast (1)
-
1
-
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
-
1
-
Hereditary cancer-predisposing syndrome (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PhyloP100
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs1057523330 ;
hg19: chr16-23619315;