Submissions for variant NM_024675.4(PALB2):c.1633G>T (p.Glu545Ter)

gnomAD frequency: 0.00001  dbSNP: rs180177103

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131237	SCV000186192	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-25	criteria provided, single submitter	clinical testing	The p.E545* pathogenic mutation (also known as c.1633G>T), located in coding exon 4 of the PALB2 gene, results from a G to T substitution at nucleotide position 1633. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This mutation was reported in a German woman who was diagnosed at the age of 83 years with bilateral invasive ductal carcinoma (IDC) with estrogen and progesterone receptor negative tumors (T2N1M0 and T2N0M0). She did not have an apparent family history of breast cancer, but reportedly her maternal grandmother suffered from stomach cancer and her sister died at the age of 67 from a cancer of unknown origin (Bogdanova N et al. Breast Cancer Res Treat. 2011 Apr;126:545-50). This alteration was also seen in a cohort of 1479 patients who underwent PALB2 genetic testing for hereditary breast cancer after previously testing negative for BRCA1 and BRCA2 mutations (Fernandes PH et al. Cancer. 2014 Apr;120:963-7). Additionally, this mutation was identified in a cohort of 80 Portuguese patients with a family history of breast and/or ovarian cancer who underwent multi-gene panel testing after testing negative for the BRCA1 and BRCA2 Portuguese founder mutations (Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56). 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.
GeneDx	RCV000255843	SCV000322076	pathogenic	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in the heterozygous state in individuals with a personal and/or family history of breast and/or pancreatic cancer (Bogdanova et al., 2011; Fernandes et al., 2014; Pinto et al., 2016; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 21165770, 24415441, 24870022, 27553368, 22692731, 23935381, 24763289, 25525159, 28152038, 34567246, 36988593, 29922827, 32885271)
Counsyl	RCV000114484	SCV000489387	pathogenic	Familial cancer of breast	2016-10-04	criteria provided, single submitter	clinical testing
Invitae	RCV000114484	SCV000550694	pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu545*) 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 (rs180177103, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21165770, 24415441). ClinVar contains an entry for this variant (Variation ID: 126611). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255843	SCV000601737	pathogenic	not provided	2016-11-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131237	SCV000690795	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least four individuals affected with breast cancer (PMID: 21165770, 24415441, 27553368, 33471991; Leiden Open Variation Database DB-ID PALB2_010079). This variant has been identified in 1/251444 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000255843	SCV001450081	pathogenic	not provided	2020-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114484	SCV004019761	pathogenic	Familial cancer of breast	2023-04-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000114484	SCV004202077	pathogenic	Familial cancer of breast	2023-09-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529917	SCV004717376	pathogenic	PALB2-related disorder	2023-11-13	criteria provided, single submitter	clinical testing	The PALB2 c.1633G>T variant is predicted to result in premature protein termination (p.Glu545*). This variant has been reported to be causative for breast cancer (Fernandes et al. 2014. PubMed ID: 24415441). This variant has also been reported in an individual with bilateral invasive ductal carcinoma with estrogen and progesterone receptor negative tumors (Bogdanova et al. 2011. PubMed ID: 21165770). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23646234-C-A). This variant has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/126611/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Leiden Open Variation Database	RCV000114484	SCV001193127	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357967	SCV001553581	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Glu545X variant was identified in 3 of 3364 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Bogdanova 2011, Fernandes 2014). The variant was also identified in dbSNP (ID: rs180177103) as With Pathogenic allele, ClinVar (classified as pathogenic by Ambry Genetics, GeneDx, Counsyl, Invitae), LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 1 of 246250 chromosomes at a frequency of 0.000004 (Genome Aggregation Consortium Feb 27, 2017). The p.Glu545X variant leads to a premature stop codon at position 545, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in breast cancer and is the type of variant expected to cause the disorder. In addition, the variant was found in a patient diagnosed at the age of 83 years as having bilateral invasive ductal carcinoma (IDC) with estrogen and progesterone receptor negative tumors (Bogdanova 2011). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003162529	SCV002758150	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research