Submissions for variant NM_024675.4(PALB2):c.1424dup (p.Arg476fs)

dbSNP: rs1555461294

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461710	SCV000550739	pathogenic	Familial cancer of breast	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg476Lysfs*11) 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 breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 410179). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657445	SCV000779180	pathogenic	not provided	2022-07-20	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 referred for genetic testing at GeneDx and in published literature (Tung et al., 2015; Hu et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25186627, 29922827)
Mendelics	RCV000709386	SCV000839038	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000709386	SCV000910264	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-05	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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000461710	SCV000917936	pathogenic	Familial cancer of breast	2018-10-22	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1424dupC (p.Arg476LysfsX11) 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 (eg. c.2167_2168delAT (p.Met723fsX21), c.2607delC (p.Val870X), and c.2920_2921delAA (p.Lys974fsX5)). The variant was absent in 245906 control chromosomes (gnomAD). c.1424dupC has been reported in the literature in an individual affected with breast cancer (Tung_2015) and pancreatic cancer (Hu_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000461710	SCV001140036	pathogenic	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000709386	SCV001171806	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	clinical testing	The c.1424dupC pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a duplication of C at nucleotide position 1424, causing a translational frameshift with a predicted alternate stop codon (p.R476Kfs*11). This mutation was detected on a 25-gene panel test in a woman who was diagnosed with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This mutation has also been detected in patients with pancreatic cancer (Hu C et al. JAMA, 2018 06;319:2401-2409; Antwi SO et al. J Natl Cancer Inst, 2019 03;111:264-271). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000657445	SCV001247804	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PALB2: PVS1, PM2, PS4:Moderate
Sema4, Sema4	RCV000709386	SCV002530612	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000461710	SCV004027753	pathogenic	Familial cancer of breast	2023-07-12	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP
Myriad Genetics, Inc.	RCV000461710	SCV004188523	pathogenic	Familial cancer of breast	2023-09-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000461710	SCV004202730	pathogenic	Familial cancer of breast	2022-06-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657445	SCV004222262	pathogenic	not provided	2022-02-18	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with pancreatic cancer (PMID: 29922827 (2018)) and breast cancer (PMIDs: 29522266 (2018), 25186627 (2015)). Based on the available information, this variant is classified as pathogenic.
Leiden Open Variation Database	RCV000461710	SCV001193101	pathogenic	Familial cancer of breast	2019-12-04	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.
BRCAlab, Lund University	RCV003155944	SCV002588990	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-26	no assertion criteria provided	clinical testing