Submissions for variant NM_024675.4(PALB2):c.2590C>T (p.Pro864Ser)

gnomAD frequency: 0.00287  dbSNP: rs45568339

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487583	SCV000149998	benign	not provided	2019-05-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26564480, 28279176, 30521987, 25794774, 25666743, 20589654, 23448497, 23935836, 22052327, 22241545, 20852946, 21365267, 21618343, 21932393, 23824750, 18302019, 24728327, 24949998, 20722467, 26283626, 17200668, 26898890, 27153395, 29052111, 28717660, 29458332, 31757951, 31586400, 31636395)
Invitae	RCV000114545	SCV000166655	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116089	SCV000185113	benign	Hereditary cancer-predisposing syndrome	2014-07-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Vantari Genetics	RCV000116089	SCV000267065	likely benign	Hereditary cancer-predisposing syndrome	2015-10-07	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114545	SCV000268014	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000116089	SCV000396090	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000322970	SCV000396091	likely benign	Fanconi anemia complementation group N	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000487583	SCV000575045	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BS1:Supporting, BS3:Supporting
Genetic Services Laboratory, University of Chicago	RCV000121759	SCV000596211	benign	not specified	2019-11-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000487583	SCV000604591	benign	not provided	2023-10-19	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000487583	SCV000609691	likely benign	not provided	2017-04-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121759	SCV000807092	benign	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487583	SCV000889583	benign	not provided	2022-06-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116089	SCV000902558	benign	Hereditary cancer-predisposing syndrome	2015-10-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000114545	SCV001140001	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000487583	SCV002010968	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121759	SCV002551654	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490764	SCV002803061	likely benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-05-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149783	SCV003838712	benign	Breast and/or ovarian cancer	2021-07-27	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315619	SCV004016499	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
ITMI	RCV000121759	SCV000085957	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000114545	SCV000207345	benign	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000116089	SCV000788092	likely benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000487583	SCV001193261	likely benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
Center of Medical Genetics and Primary Health Care	RCV001269370	SCV001448728	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001269370	SCV001549397	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Pro864Ser variant was identified in 62 of 12244 proband chromosomes (frequency: 0.005) in multinational cohorts of BRCA1 and BRCA2 negative breast and breast-ovarian cancer families, male breast cancer cases, triple negative breast cancer cases, women with breast cancer who had a personal or family history of pancreatic cancer, familial pancreatic cancer, families with 2 or more prostate cancer cases, unselected breast and ovarian cancers, and hereditary prostate cancer families; and was identified in 14 of 3250 control chromosomes (freq. 0.004) (Balia 2010, Blanco 2012, Catucci 2014, Ding 2011, Downs 2015 , Garcia 2009, Guenard 2010, Hofstatter 2011, Hellebrand 2011, Rahman 2007, Sauty de Chalon 2010, Teo 2013, Zheng 2012, Zhen 2015, Adank 2011, Aoude 2014, Papi 2010). The variant was also identified in dbSNP (ID: rs45568339) as “Other”, ClinVar (classified as benign by Invitae, Ambry Genetics, Pathway Genomics; likely benign by GeneDx, Vantari Genetics, Illumina, PALB2 database, Cancer Genetics Laboratory, Peter MacCallum Cancer Center; classification not provided by ITMI), Clinvitae (with conflicting interpretations of pathogenicity), LOVD 3.0 (19X), and Zhejiang Colon Cancer Database (3X); and was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 755 (2 homozygous) of 277236 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following population at a frequency greater than 1%: Ashkenazi Jewish* in 113 of 10152 chromosomes (freq: 0.011). The p.Pro864Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001572628	SCV001792257	uncertain significance	Breast carcinoma	2021-08-19	no assertion criteria provided	clinical testing	Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000487583	SCV001800767	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000487583	SCV001807728	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000487583	SCV001905888	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000487583	SCV001932113	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487583	SCV001954511	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487583	SCV001972018	likely benign	not provided		no assertion criteria provided	clinical testing