Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000704651 | SCV003915583 | pathogenic | Familial cancer of breast | 2023-04-05 | reviewed by expert panel | curation | The c.532del (p.Glu178fs) variant in PALB2 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 4 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant is absent in gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM2_Supporting, PM5_Supporting) |
| Invitae | RCV000704651 | SCV000833607 | pathogenic | Familial cancer of breast | 2022-05-04 | criteria provided, single submitter | clinical testing | This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28779002). This sequence change creates a premature translational stop signal (p.Glu178Asnfs*15) 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). ClinVar contains an entry for this variant (Variation ID: 580962). For these reasons, this variant has been classified as Pathogenic. |
| Color Diagnostics, |
RCV001186986 | SCV001353640 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-15 | criteria provided, single submitter | clinical testing | This variant deletes 1 nucleotide in exon 4 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 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. |
| Ambry Genetics | RCV001186986 | SCV002647023 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-05-24 | criteria provided, single submitter | clinical testing | The c.532delG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 532, causing a translational frameshift with a predicted alternate stop codon (p.E178Nfs*15). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med, 2021 02;384:428-439). 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. |
| Myriad Genetics, |
RCV000704651 | SCV004186180 | pathogenic | Familial cancer of breast | 2023-09-06 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Baylor Genetics | RCV000704651 | SCV004202796 | pathogenic | Familial cancer of breast | 2020-10-16 | criteria provided, single submitter | clinical testing |