rs730881869
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.2727_2728del(p.Thr911LeufsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L909L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024675.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2727_2728del | p.Thr911LeufsTer16 | frameshift_variant | 7/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2727_2728del | p.Thr911LeufsTer16 | frameshift_variant | 7/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251482Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135920
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461862Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727232
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Feb 24, 2018 | This c.2727_2728delTT (p.Thr911Leufs*16) frameshift variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two unrelated breast cancer patients (PMID 26681312 and 28724667). Moreover, four independent genetic diagnostic laboratories have categorized this variant as pathogenic/likely pathogenic (ClinVar database). Mono-allelic loss of function variants in the PALB2 gene have been associated with susceptibility to breast cancer and pancreatic cancer. Bi-allelic loss of function variants in this gene are associated with Fanconi anemia, complementation group N (OMIM 610832). This variant in the PALB2 gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 27, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 13, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change creates a premature translational stop signal (p.Thr911Leufs*16) 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 present in population databases (rs730881869, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182742). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 11, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2023 | 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Lowery et al., 2018; Sun et al., 2017); This variant is associated with the following publications: (PMID: 28724667, 26681312, 29506128, 31447099, 32546565, 29922827, 33804961) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2021 | The c.2727_2728delTT pathogenic mutation, located in coding exon 7 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 2727 to 2728, causing a translational frameshift with a predicted alternate stop codon (p.T911Lfs*16). This alteration has been identified in individuals diagnosed with breast cancer and a pancreatic exocrine neoplasm (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 04, 2023 | This variant deletes 2 nucleotides in exon 7 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. This variant has been reported in individuals affected with breast cancer (PMID: 26681312, 28724667, 31768816) and pancreatic cancer (PMID: 29506128). This variant has been identified in 1/251482 chromosomes 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. - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 27, 2021 | - - |
PALB2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 01, 2024 | The PALB2 c.2727_2728delTT variant is predicted to result in a frameshift and premature protein termination (p.Thr911Leufs*16). This variant has been reported in individuals with breast cancer (Supplementary Table S3, Sun et al. 2017. PubMed ID: 28724667), exocrine pancreatic neoplasm (Lowery et al. 2018. PubMed ID: 29506128) and ovarian cancer (Supplementary Table 3, Song et al. 2021. PubMed ID: 32546565). This variant was identified in an individual referred for next-generation cancer panel testing and was classified as pathogenic (Supplementary Table S1, Susswein et al. 2016. PubMed ID: 26681312). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182742). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2019 | Variant summary: PALB2 c.2727_2728delTT (p.Thr911LeufsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2920_2921delAA, p.Lys974fsX5; c.3113G>A, p.Trp1038X). The variant allele was found at a frequency of 4.1e-06 in 246270 control chromosomes. c.2727_2728delTT has been reported in the literature in individuals affected with breast and pancreatic cancer (Lowery_2018, Sun_2017, Susswein_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
PALB2-Related Disorders Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 12-07-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at