rs1555461488
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.1032_1033dupCT(p.Leu345SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L345L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0400
Publications
1 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: ClinGen, Ambry Genetics
- Fanconi anemia complementation group NInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 3Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- familial ovarian cancerInheritance: AD Classification: MODERATE Submitted by: ClinGen
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23635512-A-AAG is Pathogenic according to our data. Variant chr16-23635512-A-AAG is described in ClinVar as Pathogenic. ClinVar VariationId is 492143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | MANE Select | c.1032_1033dupCT | p.Leu345SerfsTer2 | frameshift | Exon 4 of 13 | NP_078951.2 | ||
| PALB2 | NM_001407296.1 | c.972_973dupCT | p.Leu325SerfsTer2 | frameshift | Exon 3 of 12 | NP_001394225.1 | |||
| PALB2 | NM_001407297.1 | c.1032_1033dupCT | p.Leu345SerfsTer2 | frameshift | Exon 4 of 12 | NP_001394226.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | TSL:1 MANE Select | c.1032_1033dupCT | p.Leu345SerfsTer2 | frameshift | Exon 4 of 13 | ENSP00000261584.4 | ||
| PALB2 | ENST00000568219.5 | TSL:1 | c.147_148dupCT | p.Leu50SerfsTer2 | frameshift | Exon 4 of 13 | ENSP00000454703.2 | ||
| PALB2 | ENST00000561514.3 | TSL:5 | c.1038_1039dupCT | p.Leu347SerfsTer2 | frameshift | Exon 4 of 13 | ENSP00000460666.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461538Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727064 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1461538
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727064
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:
33424
American (AMR)
AF:
AC:
0
AN:
44658
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26126
East Asian (EAS)
AF:
AC:
0
AN:
39692
South Asian (SAS)
AF:
AC:
0
AN:
86206
European-Finnish (FIN)
AF:
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1111888
Other (OTH)
AF:
AC:
0
AN:
60374
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
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
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Familial cancer of breast (3)
2
-
-
Hereditary cancer-predisposing syndrome (2)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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