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

gnomAD frequency: 0.00004  dbSNP: rs373478248

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123338	SCV000166651	benign	Familial cancer of breast	2025-02-04	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	This alteration is classified as likely 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.
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	2024-08-22	criteria provided, single submitter	clinical testing	The PALB2 c.2289G>C (p.Leu763Phe) variant has been reported in individuals with breast cancer (PMID: 23977390 (2013), 25186627 (2015), 28779002 (2017), 28825143 (2017), 30287823 (2018), 32068069 (2020), 35218119 (2022)). This variant has also been observed in reportedly healthy individuals (PMIDs: 30287823 (2018), 36243179 (2022), 35218119 (2022), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared)). An experimental study indicated this variant is not damaging to homology-directed DNA repair activity of PALB2 (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.0007 (14/19950 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212808	SCV002760827	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV004528842	SCV004108645	likely benign	PALB2-related disorder	2024-09-23	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).