Submissions for variant NM_024675.4(PALB2):c.3456dup (p.Pro1153fs)

dbSNP: rs587776426

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000133488	SCV000150015	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Antoniou et al., 2014; Couch et al., 2015; Tung et al., 2015; Schoolmeester et al., 2017; Dudley et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26681312, 29922827, 25099575, 25452441, 28709830, 29360161, 25186627, 34326862)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200796	SCV000253721	pathogenic	Familial cancer of breast	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro1153Thrfs*4) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the PALB2 protein. 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: 25099575, 25452441, 26681312). ClinVar contains an entry for this variant (Variation ID: 128142). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000116106	SCV000275762	pathogenic	Hereditary cancer-predisposing syndrome	2025-01-10	criteria provided, single submitter	clinical testing	The c.3456dupA pathogenic mutation, located in coding exon 13 of the PALB2 gene, results from a duplication of A at nucleotide position 3456, causing a translational frameshift with a predicted alternate stop codon (p.P1153Tfs*4). This alteration occurs at the 3' terminus of the PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 3% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This pathogenic mutation has been identified in multiple individuals with a personal history of breast cancer and a family history of breast and/or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Tung N et al. Cancer 2015 Jan;121(1):25-33; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Schoolmeester JK et al. Hum. Pathol. 2017 Jul;70:14-26; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Counsyl	RCV000200796	SCV000677797	pathogenic	Familial cancer of breast	2017-01-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116106	SCV000905188	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 13 of the PALB2 gene, creating a frameshift and premature translation stop signal in the last coding exon. The mutant protein is expected to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted WD40 domain that is important for PALB2 function (PMID: 31757951, 33139182). This variant has been reported in individuals affected with breast cancer (PMID: 25099575, 25186627, 25452441, 26681312, 28709830). 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.
Sema4, Sema4	RCV000116106	SCV002531184	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-12	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000133488	SCV002545765	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	PALB2: PVS1, PM2
Myriad Genetics, Inc.	RCV000200796	SCV004019637	pathogenic	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
PreventionGenetics, part of Exact Sciences	RCV004528808	SCV004107581	pathogenic	PALB2-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	The PALB2 c.3456dupA variant is predicted to result in a frameshift and premature protein termination (p.Pro1153Thrfs*4). This variant has been reported in individuals with breast cancer and individuals with pancreatic cancer (Table S2, Antoniou et al. 2014. PubMed ID: 25099575; Table 1, Schoolmeester et al. 2017. PubMed ID: 28709830; Table 2, Dudley et al. 2018. PubMed ID: 29360161; eTable 3, Hu et al. 2018. PubMed ID: 29922827; Supplement, Tung et al. 2014. PubMed ID: 25186627; Table S1, Couch et al. 2014. PubMed ID: 25452441; Table A4, Abe et al. 2019. PubMed ID: 30883245). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128142/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003155917	SCV004176977	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-29	criteria provided, single submitter	clinical testing	The PALB2 c.3456dup (p.Pro1153fs) variant has been reported in the medical literature in individuals with breast cancer (Antoniou A et al., PMID: 25099575; Couch F et al., PMID: 25452441; Susswein L et al., PMID: 26681312). This variant causes a frameshift by insertion of one nucleotide leading to premature termination. This frameshift occurs in the last exon and is not predicted to lead to nonsense mediated decay, although it disrupts the last 34 amino acids of PALB2, which are suggested to be necessary for protein function (Quinodoz M et al., PMID: 35120630). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been submitted to ClinVar as pathogenic by 11 laboratories (variation ID: 128142). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Baylor Genetics	RCV000200796	SCV004202121	pathogenic	Familial cancer of breast	2024-01-13	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000200796	SCV005016515	pathogenic	Familial cancer of breast	2023-10-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359105	SCV005913282	pathogenic	PALB2-related cancer predisposition	2021-02-16	criteria provided, single submitter	clinical testing
SNPedia	RCV000133488	SCV000188562	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Leiden Open Variation Database	RCV000200796	SCV001193414	pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000133488	SCV001740906	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000133488	SCV001905804	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV003155917	SCV002589004	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-26	no assertion criteria provided	clinical testing