Submissions for variant NM_024675.4(PALB2):c.1565del (p.Pro522fs)

dbSNP: rs1555461217

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000529207	SCV000633290	pathogenic	Familial cancer of breast	2023-05-21	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 460901). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro522Glnfs*39) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002231716	SCV002511886	likely pathogenic	Malignant tumor of breast	2022-04-26	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1565delC (p.Pro522GlnfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251488 control chromosomes. c.1565delC has been reported in the literature in at least one individual affected with Breast Cancer (Zhou_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV003380605	SCV004088822	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	The c.1565delC variant, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 1565, causing a translational frameshift with a predicted alternate stop codon (p.P522Qfs*39). This alteration was detected in 1/16501 Chinese breast cancer patients and 0/5890 female controls (Zhou J et al. Cancer, 2020 Jul;126:3202-3208). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV000529207	SCV004189333	pathogenic	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.