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rs45478192

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_024675.4(PALB2):c.2816T>G(p.Leu939Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00165 in 1,597,496 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L939F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

5
5
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:30

Conservation

PhyloP100: 5.59
Variant links:
Genes affected
PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1670264).
BP6
Variant 16-23624027-A-C is Benign according to our data. Variant chr16-23624027-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126683.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=14, Uncertain_significance=3}. Variant chr16-23624027-A-C is described in Lovd as [Benign]. Variant chr16-23624027-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PALB2NM_024675.4 linkuse as main transcriptc.2816T>G p.Leu939Trp missense_variant 8/13 ENST00000261584.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PALB2ENST00000261584.9 linkuse as main transcriptc.2816T>G p.Leu939Trp missense_variant 8/131 NM_024675.4 P1
ENST00000561764.1 linkuse as main transcriptn.547A>C non_coding_transcript_exon_variant 4/42

Frequencies

GnomAD3 genomes
AF:
0.00116
AC:
176
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00198
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000925
AC:
232
AN:
250918
Hom.:
0
AF XY:
0.000943
AC XY:
128
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.000186
Gnomad AMR exome
AF:
0.000637
Gnomad ASJ exome
AF:
0.00179
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00161
Gnomad OTH exome
AF:
0.000817
GnomAD4 exome
AF:
0.00170
AC:
2460
AN:
1445198
Hom.:
4
Cov.:
29
AF XY:
0.00164
AC XY:
1180
AN XY:
719916
show subpopulations
Gnomad4 AFR exome
AF:
0.000212
Gnomad4 AMR exome
AF:
0.000582
Gnomad4 ASJ exome
AF:
0.00207
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000169
Gnomad4 NFE exome
AF:
0.00207
Gnomad4 OTH exome
AF:
0.00155
GnomAD4 genome
AF:
0.00116
AC:
176
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.000980
AC XY:
73
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00198
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00203
Hom.:
0
Bravo
AF:
0.00115
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00337
AC:
13
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00233
AC:
20
ExAC
AF:
0.000939
AC:
114
EpiCase
AF:
0.00213
EpiControl
AF:
0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:30
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:13
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 11, 2016Variant 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. -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 25, 2023- -
Likely benign, no assertion criteria providedcurationLeiden Open Variation DatabaseMay 13, 2019Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -
Likely benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024PALB2: BP1, BS1:Supporting, BS2 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 06, 2020- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:5
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 06, 2015- -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Jan 16, 2018- -
Likely benign, criteria provided, single submittercurationSema4, Sema4Mar 08, 2021- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 20, 2014This 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. -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsNov 19, 2018- -
Familial cancer of breast Uncertain:1Benign:5
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 31, 2023This 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. -
Uncertain significance, criteria provided, single submittercase-controlCancer Genetics Laboratory, Peter MacCallum Cancer CentreJun 01, 2015- -
Likely benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Likely benign, criteria provided, single submitterclinical testingCounsylMar 01, 2018- -
not specified Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxDec 28, 2017This 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. -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 13, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 27, 2016Variant 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. -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 25, 2023- -
Fanconi anemia complementation group N Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
PALB2-related condition Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 04, 2019This 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). -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Uncertain
0.12
Cadd
Pathogenic
27
Dann
Benign
0.96
DEOGEN2
Benign
0.14
T;T
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.72
T
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-5.1
D;D
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
.;D
Vest4
0.91
MVP
0.68
MPC
0.43
ClinPred
0.13
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs45478192; hg19: chr16-23635348; COSMIC: COSV104552826; COSMIC: COSV104552826; API