Submissions for variant NM_024675.4(PALB2):c.2816T>G (p.Leu939Trp)

gnomAD frequency: 0.00121  dbSNP: rs45478192

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417395	SCV000150001	benign	not specified	2017-12-28	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114561	SCV000166658	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116092	SCV000172799	benign	Hereditary cancer-predisposing syndrome	2014-08-20	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114561	SCV000268019	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000306515	SCV000396085	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000116092	SCV000396086	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000417395	SCV000539986	uncertain significance	not specified	2016-10-27	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in multiple individuals with breast cancer. It is present in ExAC with a MaxMAF of 0.16%. It is classified in ClinVar with 1 star by multiple submitters: VUS by GeneDx and Peter MacCallum Cancer center, and LB/B by Invitae and Ambry.
Genetic Services Laboratory, University of Chicago	RCV000417395	SCV000596219	likely benign	not specified	2017-01-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586156	SCV000601772	likely benign	not provided	2020-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116092	SCV000685981	benign	Hereditary cancer-predisposing syndrome	2015-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586156	SCV000699576	benign	not provided	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: The c.2816T>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Trp. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have not been validated via in vitro/vivo functional studies yet. This variant is found in 130/130096 control chromosomes at a frequency of 0.0009993, which is about 6 times of the maximal expected frequency of a pathogenic allele (0.0001563), suggesting this variant is likely a benign polymorphism. This variant has been reported in BRCA1/2 negative BrC/OvC patients without strong evidence for causality. In multiple studies, variant was detected in cases with comparable MAF as in tested controls (Thompson_BCR_2015, Ramus_JNCI_2015, etc) suggesting lack of causative effect. Moreover, there are at least two reported pedigrees showed lack of co-segregation of variant with disease (Damiola_Breast Can Res and Treat_2015), further supporting the neural effect of this variant. In addition, two clinical laboratories via ClinVar classified this variant as benign/likely benign, and one other clinical lab and PALB2 database via ClinVar classified this variant as VUS, all without evidence to independently evaluate. Taken together, this variant was classified as Benign variant.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116092	SCV000747822	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000114561	SCV000786127	likely benign	Familial cancer of breast	2018-03-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000114561	SCV001139996	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586156	SCV001159558	likely benign	not provided	2023-08-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586156	SCV001245836	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PALB2: BP1, BS1:Supporting, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170349	SCV001332923	likely benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000114561	SCV001440269	likely benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586156	SCV002010966	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116092	SCV002530727	likely benign	Hereditary cancer-predisposing syndrome	2021-03-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417395	SCV002551648	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114561	SCV004019226	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 in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004760375	SCV005373757	benign	Hereditary breast ovarian cancer syndrome	2024-08-13	criteria provided, single submitter	curation	According to the ClinGen ACMG PALB2 v1.1.0 criteria we chose these criteria: BP1 (supporting benign): Missense variants in PALB2 where primarily truncating variants are known to cause disease., BA1 (stand-alone benign): BA1 GnomAD v2+3 non cancer Grpmax FAF NFE >0,1%
PreventionGenetics, part of Exact Sciences	RCV004528790	SCV000807098	likely benign	PALB2-related disorder	2019-09-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
True Health Diagnostics	RCV000116092	SCV000886699	likely benign	Hereditary cancer-predisposing syndrome	2018-11-19	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000586156	SCV001193292	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356702	SCV001551943	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu939Trp variant was identified in 19 of 7014 proband chromosomes (frequency: 0.003) from individuals or families with and was present in 2 of 1568 control chromosomes (frequency: 0.0013) from healthy individuals (Catucci_2014_24556926, Garcia_2009_18302019, Guenard_2010_20722467, Hofstatter_2011, Rahman_2007_17200668, Tischkowitz_2012_22241545, Wong-Brown_2014_23824750, Hellebrand_2011_21618343). The variant was also identified in the following databases: dbSNP (ID: rs45478192) as “With other allele”, ClinVar (1x as benign by Ambry Genetics, 5x as likely benign by GeneDx, Invitae, Illumina Clinical Services, 5x as uncertain significance by Cancer Genetics Laboratory, Peter MacCallum Cancer Centre Study Description, Laboratory for Molecular Medicine and PALB2 database, Clinvitae (5x), LOVD 3.0 (16x) and Zhejiang Colon Cancer Database (2x). The variant was not identified in the Cosmic, or MutDB databases. The variant was identified in control databases in 271 of 276706 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 23938 chromosomes (freq: 0.0004), Other in 5 of 6454 chromosomes (freq: 0.0008), Latino in 22 of 34388 chromosomes (freq: 0.0006), European Non-Finnish in 215 of 126424 chromosomes (freq: 0.002), Ashkenazi Jewish in 18 of 10138 chromosomes (freq: 0.0018), European Finnish in 1 of 25770 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian, and South Asian populations. The variant was also identified by our laboratory in 1 individual with breast cancer with a co-occurring pathogenic BRCA2 variant (c.755-758delACAG, p.Asp252Valfsx24), increasing the likelihood that the p.Leu939Trp variant does not have clinical significance. In one study, researchers indicate that both the leucine amino acids at positions 931 and 939 are conserved in all species, and are located in the WD40-repeat domain responsible for binding to BRCA2 and in a region that mediates the binding with RAD51. Of these two variants, only p.Leu931Arg was not annotated and not found in controls from this study or other previously published studies. The p.Leu939Trp variant is known to be relatively common in both breast cancer patients and in healthy controls thus indicating a more likely benign classification (Catucci_2014). The p.Leu939Trp 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586156	SCV001743750	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000586156	SCV001799000	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586156	SCV001807303	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000586156	SCV001905743	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000586156	SCV001932936	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586156	SCV001956770	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586156	SCV001972797	likely benign	not provided		no assertion criteria provided	clinical testing