ClinVar Miner

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

gnomAD frequency: 0.00121  dbSNP: rs45478192
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Total submissions: 33
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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.
Invitae RCV000114561 SCV000166658 benign Familial cancer of breast 2021-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000116092 SCV000172799 benign Hereditary cancer-predisposing syndrome 2014-08-20 criteria provided, single submitter clinical testing Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;No disease association in appropriately sized case-control study(ies)
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
PreventionGenetics,PreventionGenetics RCV000586156 SCV000807098 likely benign not provided 2017-01-12 criteria provided, single submitter clinical testing
Mendelics RCV000116092 SCV000839013 likely benign Hereditary cancer-predisposing syndrome 2018-07-02 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 2020-03-27 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586156 SCV001245836 likely benign not provided 2021-10-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170349 SCV001332923 likely benign Breast and/or ovarian cancer 2019-04-09 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 RCV000114561 SCV002010966 likely benign Familial cancer of breast 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
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000417395 SCV002551648 likely benign not specified 2021-11-18 no assertion criteria provided clinical testing

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