Submissions for variant NM_024675.4(PALB2):c.654del (p.Asp219fs)

dbSNP: rs587781697

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129864	SCV000184681	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	The c.654delA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 654, causing a translational frameshift with a predicted alternate stop codon (p.D219Tfs*4). 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.
Color Diagnostics, LLC DBA Color Health	RCV000129864	SCV000292143	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-02	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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251346 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635944	SCV000757371	pathogenic	Familial cancer of breast	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp219Thrfs*4) 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 (rs587781697, 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: 141372). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000635944	SCV004189465	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	RCV000635944	SCV004202722	pathogenic	Familial cancer of breast	2022-08-11	criteria provided, single submitter	clinical testing
CZECANCA consortium	RCV001270996	SCV001451808	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358375	SCV001554090	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Asp219ThrfsX4 variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, LOVD 3.0, or the Zhejiang University Database. The variant was identified in dbSNP (ID: rs587781697) as "With Pathogenic allele", ClinVar (2x, pathogenic), and the Clinvitae database. The variant was not identified in control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.654delA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 219 and leads to a premature stop codon at position 222. This alteration is then predicted to result in 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 associated 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.