Submissions for variant NM_024675.4(PALB2):c.93dup (p.Leu32fs)

dbSNP: rs864622498

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204530	SCV000260859	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu32Thrfs*11) 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: 25452441). ClinVar contains an entry for this variant (Variation ID: 220371). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000223136	SCV000273128	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	clinical testing	The c.93dupA pathogenic mutation, located in coding exon 2 of the PALB2 gene, results from a duplication of A at nucleotide position 93, causing a translational frameshift with a predicted alternate stop codon (p.L32Tfs*11). This mutation has been detected in multiple individuals with a personal and/or family history of breast cancer (Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Pritzlaff M et al. Breast Cancer Res. Treat., 2017 02;161:575-586; Yadav S et al. Fam. Cancer, 2017 07;16:319-328; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This mutation has also been reported in a male patient with biliary cancer (Schrader KA et al. JAMA Oncol, 2016 Jan;2:104-11). 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.
GeneDx	RCV000236141	SCV000293706	pathogenic	not provided	2023-03-28	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25452441, 26556299, 27878467, 29785153, 28008555, 31159747, 31937788)
Color Diagnostics, LLC DBA Color Health	RCV000223136	SCV000690950	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 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: 25452441, 27878467, 28008555, 29785153, 37239058). 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.
GeneKor MSA	RCV000223136	SCV000821753	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single base pair insertion in exon 2 of the PALB2 mRNA, causing a frameshift after codon 32 and this creates a premature translational stop signal 11 amino acid residues later. This is expected to result in an absent or disrupted protein product. Truncating variants in the PALB2 gene are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has been described in the international literature in an individual with breast cancer (PMID: 25452441) and in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID:220371).
Mendelics	RCV000223136	SCV000839064	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000204530	SCV001140069	pathogenic	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236141	SCV002551694	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288830	SCV002579337	likely pathogenic	Pancreatic cancer, susceptibility to, 3	2021-06-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485348	SCV002787335	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-10-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204530	SCV004188471	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	RCV000204530	SCV004202671	pathogenic	Familial cancer of breast	2023-02-23	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000204530	SCV001192922	likely pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.