rs745444171
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting
The NM_024675.4(PALB2):βc.37_39delβ(p.Glu13del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000248 in 1,613,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. E13E) has been classified as Likely benign.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
PALB2
NM_024675.4 inframe_deletion
NM_024675.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.87
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
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In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 16 uncertain in NM_024675.4
PM2
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Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_024675.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.37_39del | p.Glu13del | inframe_deletion | 1/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.37_39del | p.Glu13del | inframe_deletion | 1/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151966Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247884Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134402
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461298Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726920
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151966Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74200
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2022 | This variant, c.37_39del, results in the deletion of 1 amino acid(s) of the PALB2 protein (p.Glu13del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745444171, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231830). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2023 | The c.37_39delGAG variant (also known as p.E13DEL) located in coding exon 1 of the PALB2 gene. This variant results from an in-frame GAG deletion between nucleotide positions 37 and 39. This results in the in-frame deletion of a glutamic acid residue at codon 13. This amino acid position is highly conserved through mammals. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2023 | This variant causes the deletion of one amino acid, glutamic acid, at codon 13 in the PALB2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/247884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 20, 2020 | Variant summary: PALB2 c.37_39delGAG (p.Glu13del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 8.1e-06 in 247884 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.37_39delGAG in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4357+1G>A; Internal testing). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Infiltrating duct carcinoma of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | 3DMed Clinical Laboratory Inc | Jul 29, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 08, 2019 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at