Submissions for variant NM_024675.4(PALB2):c.2192T>G (p.Leu731Ter)

dbSNP: rs1567217898

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000755035	SCV000882855	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-10-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000755035	SCV001175428	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The p.L731* pathogenic mutation (also known as c.2192T>G), located in coding exon 5 of the PALB2 gene, results from a T to G substitution at nucleotide position 2192. This changes the amino acid from a leucine to a stop codon within coding exon 5. 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.
Invitae	RCV001855858	SCV002151494	pathogenic	Familial cancer of breast	2023-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 617779). This premature translational stop signal has been observed in individual(s) with breast cancer and/or pancreatic cancer (PMID: 28709830, 32885271). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu731*) 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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001855858	SCV002762831	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_SUP, PM2_SUP
Myriad Genetics, Inc.	RCV001855858	SCV004186197	pathogenic	Familial cancer of breast	2023-09-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354086	SCV001548615	pathogenic	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Leu731* variant was not identified in the literature nor was it identified in the dbSNP, or LOVD 3.0 databases. The variant was identified in ClinVar (as likely pathogenic by Department of Molecular Diagnostics, Institute of Oncology). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Leu731* variant leads to a premature stop codon at position 731 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 related cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.