ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2289G>C (p.Leu763Phe)

gnomAD frequency: 0.00004  dbSNP: rs373478248
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 19
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123338 SCV000166651 benign Familial cancer of breast 2021-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130052 SCV000184879 likely benign Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000587948 SCV000211515 likely benign not provided 2021-02-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28678401, 26283626, 23977390, 26689913, 28825143, 28779002, 25186627, 25225064, 30287823, 29338689, 30093976, 30447919, 31636395)
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000123338 SCV000268011 uncertain significance Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Color Diagnostics, LLC DBA Color Health RCV000130052 SCV000537530 likely benign Hereditary cancer-predisposing syndrome 2019-12-13 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212808 SCV000596220 uncertain significance not specified 2016-01-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212808 SCV000699560 benign not specified 2020-10-05 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2289G>C (p.Leu763Phe) results in a non-conservative amino acid change located in the MRG15 interaction domain (Zhang_PALB2_BCRT_2017) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251480 control chromosomes, predominantly at a frequency of 0.00065 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2289G>C has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Wiltshire_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=3, VUS n=7). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212808 SCV001159692 uncertain significance not specified 2019-05-10 criteria provided, single submitter clinical testing The PALB2 c.2289G>C; p.Leu763Phe variant (rs373478248) is reported in Eastern Asian individuals with familial or sporadic breast cancer as well as healthy controls (Momozawa 2018, Zhang 2017). This variant is reported as likely benign or uncertain in ClinVar (Variation ID: 136133). It is found in the general East Asian population with an allele frequency of 0.07% (14/19950 alleles) in the Genome Aggregation Database. The leucine at codon 763 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. REFERENCES Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083 Zhang K et al. Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer. Breast Cancer Res Treat. 2017 Dec;166(3):865-873.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587948 SCV001469845 uncertain significance not provided 2021-02-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000123338 SCV001483086 uncertain significance Familial cancer of breast 2020-12-04 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798407 SCV002043591 uncertain significance Breast and/or ovarian cancer 2020-11-18 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000130052 SCV002530685 likely benign Hereditary cancer-predisposing syndrome 2021-07-11 criteria provided, single submitter curation
True Health Diagnostics RCV000130052 SCV000788091 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000123338 SCV001193209 uncertain significance Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
King Laboratory,University of Washington RCV000212808 SCV001251340 benign not specified 2019-09-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357632 SCV001553156 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Leu763Phe variant was identified in 3 of 4236 proband chromosomes (frequency: 0.0007) from Asian and Australian individuals or families with breast and ovarian cancer (Phuah 2013, Thompson 2015). The variant was also identified in dbSNP (ID: rs373478248) as With other allele, ClinVar (1x likely benign: Invitae; 4x uncertain significance: Ambry Genetics, GeneDx, Peter MacCullum Cancer Centre, Color Genomics), LOVD 3.0 (2x likely does not affect function), databases. The variant was not identified in COSMIC, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 14 of 277240 chromosomes at a frequency of 0.00005 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Leu763Phe residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000587948 SCV001979720 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000587948 SCV001980479 uncertain significance not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000587948 SCV002036174 uncertain significance not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.