Submissions for variant NM_024675.4(PALB2):c.2488del (p.Glu830fs)

dbSNP: rs876658813

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217161	SCV000274538	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-26	criteria provided, single submitter	clinical testing	The c.2488delG pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2488, causing a translational frameshift with a predicted alternate stop codon (p.E830Sfs*21). This mutation has been identified in an unaffected 45 year old woman with a family history of ovarian cancer (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107:). This mutation was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). 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	RCV000478191	SCV000566171	pathogenic	not provided	2022-04-12	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Ramus 2015, Singh 2018, Petridis 2019, Lerner-Ellis 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26315354, 29470806, 32885271, 31263054)
Color Diagnostics, LLC DBA Color Health	RCV000217161	SCV000685953	pathogenic	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 5 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 individuals affected with ovarian cancer in the literature (PMID: 26315354). This variant has been identified in 1/251294 chromosomes 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	RCV000635786	SCV000757209	pathogenic	Familial cancer of breast	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu830Serfs*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 present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with family history of ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 230859). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001782706	SCV002016529	pathogenic	Fanconi anemia complementation group N	2020-09-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000217161	SCV002530701	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150120	SCV003838714	pathogenic	Breast and/or ovarian cancer	2021-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000635786	SCV004189337	pathogenic	Familial cancer of breast	2023-09-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017527	SCV004848753	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The p.Glu830SerfsX21 variant in PALB2 has been reported in at least 3 individuals with breast or ovarian cancer (Ramus 2015 PMID: 26315354, Singh 2018 PMID: 29470806, Lerner-Ellis 2020 PMID: 32885271). It has also been identified in 0.02% (1/4836) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 230859). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 830 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PALB gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominan hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting.
Neuberg Centre For Genomic Medicine, NCGM	RCV000635786	SCV005042564	pathogenic	Familial cancer of breast		criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000478191	SCV001550909	pathogenic	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Glu830Serfs*21 variant was identified in 1 of 6472 proband chromosomes (frequency: 0.0002) from individuals or families with epithelial ovarian cancer (Ramus 2015). The variant was also identified in dbSNP (ID: rs876658813) as "With Pathogenic allele" and ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and Color). The variant was not identified in LOVD 3.0 or the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.2488del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 830 and leads to a premature stop codon at position 850. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.