ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2267_2283dup (p.His762fs)

dbSNP: rs755471995
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235770 SCV000293073 pathogenic not provided 2023-06-12 criteria provided, single submitter clinical testing 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with breast cancer and in an individual with osteosarcoma (Cerretini et al., 2019; Mirabello et al., 2020); Also reported as c.2283_2284insGCACACCCCAACTTGCT; This variant is associated with the following publications: (PMID: 29922827, 30322717, 17200668, 17200671, 17200672, 24136930, 25099575, 31446535, 32191290, 31341520, 33471991)
Ambry Genetics RCV000454296 SCV000538149 pathogenic Hereditary cancer-predisposing syndrome 2021-07-19 criteria provided, single submitter clinical testing The c.2267_2283dup17 variant, located in coding exon 5 of the PALB2 gene, results from a duplication of GCACACCCCAACTTGCT at nucleotide position 2267, causing a translational frameshift with a predicted alternate stop codon (p.H762Afs*8). This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000461617 SCV000550696 pathogenic Familial cancer of breast 2023-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His762Alafs*8) 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 (rs755471995, gnomAD 0.0009%). 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: 245890). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000454296 SCV000690836 pathogenic Hereditary cancer-predisposing syndrome 2023-05-04 criteria provided, single submitter clinical testing This variant inserts 17 nucleotides in exon 5 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, this variant has not been reported in individuals affected with hereditary cancer in the literature, but it has been detected in an individual affected with breast cancer (Color internal data). This variant has been identified in 1/251484 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.
Myriad Genetics, Inc. RCV000461617 SCV004189400 pathogenic Familial cancer of breast 2023-09-12 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 RCV000461617 SCV004202711 pathogenic Familial cancer of breast 2022-09-28 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003485569 SCV004237505 pathogenic Fanconi anemia complementation group N 2023-06-06 criteria provided, single submitter clinical testing

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