rs1555461551
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.901_907del(p.Asp301SerfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D301D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.20
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 Pathogenic. Variant got 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 16-23635638-AGGTTATC-A is Pathogenic according to our data. Variant chr16-23635638-AGGTTATC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 484224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635638-AGGTTATC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.901_907del | p.Asp301SerfsTer3 | frameshift_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.901_907del | p.Asp301SerfsTer3 | frameshift_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461792Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727198
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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1
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1461792
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1
AN XY:
727198
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 484224). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 24136930). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp301Serfs*3) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 07, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2017 | This deletion of seven nucleotides in PALB2 is denoted c.901_907delGATAACC at the cDNA level and p.Asp301SerfsX3 (D301SfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TACA[delGATAACC]TCCT. The deletion causes a frameshift which changes an Aspartic Acid to a Serine at codon 301, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PALB2 c.901_907delGATAACC has been reported in at least one individual with male breast cancer (Janatova 2013). Based on the currently available information, we consider this deletion to be a likely pathogenic variant. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2023 | The c.901_907delGATAACC pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of 7 nucleotides at nucleotide positions 901 to 907, causing a translational frameshift with a predicted alternate stop codon (p.D301Sfs*3). This alteration was reported in an individual diagnosed with breast cancer (Janatova M et al. Cancer Epidemiol. Biomarkers Prev., 2013 Dec;22:2323-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at