Submissions for variant NM_024675.4(PALB2):c.2479del (p.Thr827fs)

dbSNP: rs1597088811

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001015636	SCV001176491	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-20	criteria provided, single submitter	clinical testing	The c.2479delA pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2479, causing a translational frameshift with a predicted alternate stop codon (p.T827Hfs*24). 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.
GeneDx	RCV002466601	SCV002762304	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002551781	SCV003294259	pathogenic	Familial cancer of breast	2023-08-18	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PALB2-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 821329). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr827Hisfs*24) 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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315444	SCV004015170	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr827Hisfs*24) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is not found in gnomAD genomes. Another but similar variant affecting the same codon (p.Thr827Metfs*6) has been observed in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 29566657). ClinVar contains an entry for this variant (Variation ID: 821329). Loss-offunction variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). Therefore, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017773	SCV004848926	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The p.Thr827HisfsX24 variant in PALB2 has not been reported in individuals with hereditary breast cancer or Fanconi anemia and was absent from large population databases. The variant has been reported in ClinVar (Variation ID 821329). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 827 and leads to a premature termination codon 24 amino acids downstream. Loss of function of PALB2 is an established disease mechanism for autosomal dominant hereditary breast cancer and autosomal recessive Fanconi anemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Fanconi anemia. ACMG/AMP criteria applied: PVS1, PM2_Supporting.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003315444	SCV005438153	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2024-12-17	criteria provided, single submitter	clinical testing