rs587776421
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):βc.2920_2921delβ(p.Lys974GlufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.25
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
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 16-23623043-CTT-C is Pathogenic according to our data. Variant chr16-23623043-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 126696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23623043-CTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2920_2921del | p.Lys974GlufsTer5 | frameshift_variant | 9/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2920_2921del | p.Lys974GlufsTer5 | frameshift_variant | 9/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.420-855_420-854del | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461864Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727236
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Lys974Glufs*5) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21285249, 28779002). ClinVar contains an entry for this variant (Variation ID: 126696). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21285249, 28779002, 25099575, 23935381, 28152038, 26898890, 26681312, 24870022, 33084842) - |
Pathogenic, no assertion criteria provided | literature only | SNPedia | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 09, 2021 | This variant deletes 2 nucleotides in exon 9 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with breast cancer (PMID: 21285249, 26681312, 26898890, 28779002) and is reported to segregate with disease (PMID: 26898890). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 27, 2022 | The c.2920_2921delAA pathogenic mutation, located in coding exon 9 of the PALB2 gene, results from a deletion of 2 nucleotides between positions 2920 and 2921, causing a translational frameshift with a predicted alternate stop codon (p.K974EFS*5). This alteration has been previously reported in individuals with personal and family histories of breast cancer (Casadei S et al. Cancer Res. 2011 Mar; 71(6):2222-9; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506; Susswein LR et al. Genet Med. 2016 Aug;18(8):823-32; Decker B et al. J Med Genet. 2017 Nov;54(11):732-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 19, 2022 | - - |
Fanconi anemia complementation group N Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 05, 2019 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2017 | Variant summary: The PALB2 c.2920_2921delAA (p.Lys974Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent PALB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 123322 control chromosomes. Multiple publications cite the variant in affected individuals, along with multiple clinical diagnostic laboratories/reputable databases classifying the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." - |
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