Submissions for variant NM_024675.4(PALB2):c.2993G>A (p.Gly998Glu)

gnomAD frequency: 0.01717  dbSNP: rs45551636

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114578	SCV000153916	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121762	SCV000170861	benign	not specified	2013-10-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000127300	SCV000212703	benign	Hereditary cancer-predisposing syndrome	2014-06-10	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	RCV000127300	SCV000267064	likely benign	Hereditary cancer-predisposing syndrome	2015-10-26	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114578	SCV000268020	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
PreventionGenetics, part of Exact Sciences	RCV000121762	SCV000314375	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000372394	SCV000396078	benign	Fanconi anemia complementation group N	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000114578	SCV000488456	benign	Familial cancer of breast	2016-04-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000127300	SCV000576427	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755594	SCV000604596	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000114578	SCV001139992	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	RCV000755594	SCV002010962	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225305	SCV002504921	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127300	SCV002530743	benign	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121762	SCV002551641	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498483	SCV002810173	likely benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-08-06	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315621	SCV004016493	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114578	SCV004019228	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
ITMI	RCV000121762	SCV000085960	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000114578	SCV000207351	benign	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000127300	SCV000788094	likely benign	Hereditary cancer-predisposing syndrome	2018-02-23	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000755594	SCV001193320	benign	not provided	2019-08-07	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Melissa DeRycke.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356229	SCV001551343	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Gly998Glu variant was identified in 268 of 12272 proband chromosomes (freq 0.022) in multinational cohorts of BRCA1 and BRCA2 negative breast and breast-ovarian cancer families, male breast cancer cases, women with breast cancer who had a personal or family history of pancreatic cancer, families with 2 or more prostate cancer cases, unselected breast and ovarian cancers, and American hereditary prostate cancer families; and was identified in 129 of 7352 control chromosomes (freq. 0.018) (Balia 2010, Blanco 2012, Bogdanova 2011, Cao 2009, Catucci 2014, Ding 2011, Downs 2015 , Garcia 2009, Guenard 2010, Hofstatter 2011, Kuusisto 2011, Leyton 2015 , Pakkanen 2009, Prokofyeva 2012, Hellebrand 2011, Rahman 2007, Sauty de Chalon 2010, Silvestri 2010, Sluiter 2009, Teo 2013, Wong 2011, Tischkowitz 2008, Zheng 2012). Blanco et al (2012) identified the variant in 6 index cases, which also had 5 other PALB2 variants, with co-segregation analysis in one of the carriers suggesting that all 6 variants constituted a haplotype. In a study looking at BRCA1 positive and BRCA negative families, the PALB2 variant was found in 2 families who carried different BRCA1 mutations (332-11T-Gins59-ter75, and 300Cys-Gly (T-G)) (Downs 2015 ). In their study, Rahman et al (2007) found no overall evidence that PALB2 missense variants confer susceptibility to breast cancer, with 23% affected individuals and 24% controls carrying at least one nonsynonymous missense variant. The variant was also identified in dbSNP (ID: rs45551636) as “other” allele, Clinvitae database (classifications benign, likely benign, conflicting interpretations of pathogenicity), Fanconi Anemia Mutation Database (LOVD), the ClinVar database (classifications benign: Invitae, Ambry Genetics, Prevention Genetics, Counsyl, GeneDx, Pathway Genomics, PALB2 database , likely benign: Vantari Genetics, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Illumina Clinical Services Laboratory , and not provided: ITMI submitters). The variant was identified in control databases in 1917 of 121404 chromosomes at a frequency of 0.01579 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 237 of 10150 chromosomes (freq: 0.023), European (Non-Finnish) in 2781 of 126704 chromosomes (freq: 0.022), Other in 129 of 6466 chromosomes (freq: 0.02), European (Finnish) in 481 of 25784 chromosomes (freq: 0.019), Latino in 471 of 34418 chromosomes (freq: 0.014). The p.Gly998 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000755594	SCV001798829	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121762	SCV001807990	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121762	SCV001905909	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121762	SCV001958368	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153364	SCV003843585	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing