rs45478192
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
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
NM_024675.4 missense
Scores
5
7
7
Clinical Significance
Conservation
PhyloP100: 5.59
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 Benign. Variant got -7 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: {Likely_benign=14, Benign=6, 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].
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.2816T>G | p.Leu939Trp | missense_variant | 8/13 | ENST00000261584.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.2816T>G | p.Leu939Trp | missense_variant | 8/13 | 1 | NM_024675.4 | P1 | |
| ENST00000561764.1 | n.547A>C | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes 0.00116 AC: 176AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000925 AC: 232AN: 250918Hom.: 0 AF XY: 0.000943 AC XY: 128AN XY: 135736
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GnomAD4 exome AF: 0.00170 AC: 2460AN: 1445198Hom.: 4 Cov.: 29 AF XY: 0.00164 AC XY: 1180AN XY: 719916
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GnomAD4 genome 0.00116 AC: 176AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000980 AC XY: 73AN XY: 74478
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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, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 06, 2020 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PALB2: BP1, BS1:Supporting, BS2 - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Likely benign, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2016 | 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. - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 25, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:5
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 20, 2014 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 16, 2018 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Nov 19, 2018 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 08, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 06, 2015 | - - |
Familial cancer of breast Uncertain:1Benign:5
| Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Mar 01, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
not specified Uncertain:1Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 27, 2016 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 13, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2017 | 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. - |
PALB2-related disorder Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2019 | 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). - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 25, 2023 | - - |
Fanconi anemia complementation group N Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
MVP
0.68
MPC
0.43
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at