Submissions for variant NM_024675.4(PALB2):c.976dup (p.Ser326fs)

dbSNP: rs1555461517

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000454170	SCV000538185	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-15	criteria provided, single submitter	clinical testing	The c.976dupT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a duplication of T at nucleotide position 976, causing a translational frameshift with a predicted alternate stop codon (p.S326Ffs*6). This mutation has been previously reported in an individual diagnosed with breast cancer at age 44 with a family history of pancreatic cancer in two relatives (Barnes CA et al. Fam. Cancer, 2018 01;17:101-111). 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.
Invitae	RCV000635689	SCV000757110	pathogenic	Familial cancer of breast	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser326Phefs*6) 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: 402313). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000635689	SCV004188532	pathogenic	Familial cancer of breast	2023-09-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV000454170	SCV004357952	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	This variant inserts 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 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.