Submissions for variant NM_024675.4(PALB2):c.2821del (p.Ile941fs)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003182755	SCV003867690	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	The c.2821delA pathogenic mutation, located in coding exon 8 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2821, causing a translational frameshift with a predicted alternate stop codon (p.I941Sfs*21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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, Inc.	RCV003455777	SCV004186210	pathogenic	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Invitae	RCV003455777	SCV004244904	pathogenic	Familial cancer of breast	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile941Serfs*21) 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 variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2453300). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003182755	SCV004357834	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 8 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 PALB2-related disorders in the literature. 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.