Submissions for variant NM_024675.4(PALB2):c.820dup (p.Thr274fs)

dbSNP: rs1555461611

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657281	SCV000779012	pathogenic	not provided	2024-12-23	criteria provided, single submitter	clinical testing	Identified in individuals with a personal history of breast cancer (PMID: 30287823, 32566746); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30287823, 32566746)
Ambry Genetics	RCV001027286	SCV001189821	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-16	criteria provided, single submitter	clinical testing	The c.820dupA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a duplication of A at nucleotide position 820, causing a translational frameshift with a predicted alternate stop codon (p.T274Nfs*9). This alteration has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and 0 in 11241 female controls of Japanese ancestry (Momozawa et al. Nat Commun 2018 10;9(1):4083). 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030717	SCV001193685	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV003451585	SCV004189451	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	RCV001027286	SCV004357968	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-29	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. This variant has been reported in a breast cancer case-control study in 1/7051 cases and absent in 0/11241 unaffected individuals (PMID: 30287823). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003451585	SCV004551735	pathogenic	Familial cancer of breast	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr274Asnfs*9) 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 premature translational stop signal has been observed in individual(s) with features of hereditary breast and ovarian cancer syndrome (PMID: 30287823, 32566746). ClinVar contains an entry for this variant (Variation ID: 545758). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001030717	SCV004847401	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The p.Thr274AsnfsX9 variant in PALB2 has been reported in at least 1 individual with a PALB2-associated cancer, such as breast cancer (Momozawa 2018 PMID: 30287823, Kaneyasu 2020 PMID: 32566746). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 545758) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 274 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PALB2 gene is an established disease mechanism in autosomal dominant PALB2-associated cancers, including breast cancer. In the compound heterozygous or homozygous state, these variants are associated with 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 PALB2-related cancers. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.
Leiden Open Variation Database	RCV000657281	SCV001193024	pathogenic	not provided	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.