Submissions for variant NM_024675.4(PALB2):c.3048del (p.Phe1016fs)

dbSNP: rs515726104

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129785	SCV000184594	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	clinical testing	The c.3048delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3048, causing a translational frameshift with a predicted alternate stop codon (p.F1016Lfs*17). This alteration has been reported in an African American woman diagnosed with invasive breast cancer at age 60 who also had a family history of pancreatic cancer (Zheng Y et al. Cancer 2012;118:1362-70). This variant was also reported in an African American woman with triple negative breast cancer diagnosed over the age of 45 (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9). 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.
Counsyl	RCV000114587	SCV000489479	pathogenic	Familial cancer of breast	2016-10-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000412897	SCV000490686	pathogenic	not provided	2022-02-04	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 (Zheng 2012, Tung 2015); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21932393, 25186627, 25428789, 24870022, 22692731, 29625052, 26689913, 32339256, 30287823, 30128536, 29486991)
Invitae	RCV000114587	SCV000633397	pathogenic	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1016Leufs*17) 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 (rs515726104, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21932393, 25428789). ClinVar contains an entry for this variant (Variation ID: 126707). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129785	SCV000686004	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21932393, 25428789, 27153395, 30128536, 30287823). In a breast cancer case-control study, this variant was identified in 1/7051 female breast cancer cases and was absent in any controls (PMID: 30287823). This variant has been identified in 1/246228 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000412897	SCV001134549	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	The PALB2 c.3048del (p.Phe1016Leufs*17) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32339256 (2020), 30128536 (2019), 30287823 (2018), 29486991 (2018), 28888541 (2017), 27153395 (2016), 25428789 (2015), 25186627 (2015), 21932393 (2012), 22692731 (2012)), head and neck squamous cell carcinoma (PMIDs: 29625052 (2018), 26689913 (2015)), as well as in healthy individuals (PMID: 29922827 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193464	SCV001362315	pathogenic	Hereditary breast ovarian cancer syndrome	2019-12-09	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3048delT (p.Phe1016LeufsX17) 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. The variant was absent in 251448 control chromosomes (gnomAD). c.3048delT has been reported in the literature in individuals affected with breast and/or ovarian cancer (Zheng_2012, Tung_2014, Barrington_2018, Lu_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Division of Medical Genetics, University of Washington	RCV000114587	SCV001424809	pathogenic	Familial cancer of breast	2019-06-17	criteria provided, single submitter	clinical testing	This variant leads to a translational frameshift and the introduction of a premature termination codon 17 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PALB2 is a well-established mechanism of disease for increased breast cancer risk (Rahman 2007, Janatova 2013, Antoniou 2014). This variant has an allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with breast cancer (Zheng 2012, Churpek 2015, Tung 2015). Thus, this variant is interpreted as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000412897	SCV002067396	likely pathogenic	not provided	2019-11-15	criteria provided, single submitter	clinical testing	DNA sequence analysis demonstrated the presence of a heterozygous 1 base-pair deletion in the PALB2 gene, c.3048del. This sequence change results in an amino acid frameshift and creates a premature stop codon 16 amino acids downstream of the mutation, p.Phe1016Leufs*17. This deletion is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PALB2 protein with potentially abnormal function. This sequence change has not been described in population databases (gnomAD, ExAC). The c.3048del sequence change has been identified in an African American woman with breast cancer, and a family history of colorectal cancer, leukemia, and pancreatic cancer (PMID: 21932393). This sequence change is likely causative of susceptibility to breast cancer and pancreatic cancer, however functional studies have not been performed to prove this conclusively.
Fulgent Genetics, Fulgent Genetics	RCV002477271	SCV002778954	pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-11-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114587	SCV004019636	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.
Baylor Genetics	RCV000114587	SCV004202056	pathogenic	Familial cancer of breast	2023-10-04	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114587	SCV001193333	pathogenic	Familial cancer of breast	2020-02-28	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.