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rs45568339

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_024675.4(PALB2):c.2590C>T(p.Pro864Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,614,176 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P864H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0035 ( 11 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

3
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:31O:1

Conservation

PhyloP100: 0.823
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 Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00803414).
BP6
Variant 16-23626394-G-A is Benign according to our data. Variant chr16-23626394-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 126669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626394-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PALB2NM_024675.4 linkuse as main transcriptc.2590C>T p.Pro864Ser missense_variant 7/13 ENST00000261584.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PALB2ENST00000261584.9 linkuse as main transcriptc.2590C>T p.Pro864Ser missense_variant 7/131 NM_024675.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00281
AC:
427
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00101
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00458
Gnomad ASJ
AF:
0.0121
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00376
Gnomad OTH
AF:
0.00717
GnomAD3 exomes
AF:
0.00284
AC:
715
AN:
251474
Hom.:
2
AF XY:
0.00292
AC XY:
397
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.000615
Gnomad AMR exome
AF:
0.00295
Gnomad ASJ exome
AF:
0.0114
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000359
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00392
Gnomad OTH exome
AF:
0.00489
GnomAD4 exome
AF:
0.00348
AC:
5084
AN:
1461876
Hom.:
11
Cov.:
31
AF XY:
0.00352
AC XY:
2562
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000657
Gnomad4 AMR exome
AF:
0.00340
Gnomad4 ASJ exome
AF:
0.0122
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000429
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.00387
Gnomad4 OTH exome
AF:
0.00371
GnomAD4 genome
AF:
0.00279
AC:
425
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.00240
AC XY:
179
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00101
Gnomad4 AMR
AF:
0.00451
Gnomad4 ASJ
AF:
0.0121
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00376
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.00427
Hom.:
2
Bravo
AF:
0.00304
TwinsUK
AF:
0.00593
AC:
22
ALSPAC
AF:
0.00285
AC:
11
ESP6500AA
AF:
0.000910
AC:
4
ESP6500EA
AF:
0.00314
AC:
27
ExAC
AF:
0.00266
AC:
323
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00425
EpiControl
AF:
0.00533

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:31Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:13
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
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 testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 17, 2022- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsApr 27, 2017- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024PALB2: BP4, BS1:Supporting, BS3:Supporting -
Likely benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Likely benign, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 22, 2019This variant is associated with the following publications: (PMID: 26564480, 28279176, 30521987, 25794774, 25666743, 20589654, 23448497, 23935836, 22052327, 22241545, 20852946, 21365267, 21618343, 21932393, 23824750, 18302019, 24728327, 24949998, 20722467, 26283626, 17200668, 26898890, 27153395, 29052111, 28717660, 29458332, 31757951, 31586400, 31636395) -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 19, 2023- -
Hereditary cancer-predisposing syndrome Benign:5
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsJan 12, 2018- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 11, 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. -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 15, 2015- -
Likely benign, criteria provided, single submitterclinical testingVantari GeneticsOct 07, 2015- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Familial cancer of breast Benign:4
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, no assertion criteria providedclinical testingPathway GenomicsNov 06, 2014- -
Likely benign, criteria provided, single submittercase-controlCancer Genetics Laboratory, Peter MacCallum Cancer CentreJun 01, 2015- -
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
not specified Benign:3Other:1
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 29, 2019- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 23, 2016- -
Malignant tumor of breast Benign:2
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The PALB2 p.Pro864Ser variant was identified in 62 of 12244 proband chromosomes (frequency: 0.005) in multinational cohorts of BRCA1 and BRCA2 negative breast and breast-ovarian cancer families, male breast cancer cases, triple negative breast cancer cases, women with breast cancer who had a personal or family history of pancreatic cancer, familial pancreatic cancer, families with 2 or more prostate cancer cases, unselected breast and ovarian cancers, and hereditary prostate cancer families; and was identified in 14 of 3250 control chromosomes (freq. 0.004) (Balia 2010, Blanco 2012, Catucci 2014, Ding 2011, Downs 2015 , Garcia 2009, Guenard 2010, Hofstatter 2011, Hellebrand 2011, Rahman 2007, Sauty de Chalon 2010, Teo 2013, Zheng 2012, Zhen 2015, Adank 2011, Aoude 2014, Papi 2010). The variant was also identified in dbSNP (ID: rs45568339) as “Other”, ClinVar (classified as benign by Invitae, Ambry Genetics, Pathway Genomics; likely benign by GeneDx, Vantari Genetics, Illumina, PALB2 database, Cancer Genetics Laboratory, Peter MacCallum Cancer Center; classification not provided by ITMI), Clinvitae (with conflicting interpretations of pathogenicity), LOVD 3.0 (19X), and Zhejiang Colon Cancer Database (3X); and was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 755 (2 homozygous) of 277236 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following population at a frequency greater than 1%: Ashkenazi Jewish* in 113 of 10152 chromosomes (freq: 0.011). The p.Pro864Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 this variant meets our laboratory's criteria to be classified as benign. -
Benign, no assertion criteria providedclinical testingCenter of Medical Genetics and Primary Health Care-- -
Breast carcinoma Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingMedical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health SciencesAug 19, 2021Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative -
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 17, 2022- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJul 27, 2021- -
Breast-ovarian cancer, familial, susceptibility to, 5 Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.48
Cadd
Benign
19
Dann
Uncertain
0.98
DEOGEN2
Benign
0.0087
T;T
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.071
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.0080
T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.90
N
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-3.5
D;D
Sift
Benign
0.12
T;T
Sift4G
Benign
0.72
T;T
Polyphen
0.58
.;P
Vest4
0.31
MVP
0.55
MPC
0.12
ClinPred
0.029
T
GERP RS
2.8
Varity_R
0.25
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs45568339; hg19: chr16-23637715; COSMIC: COSV99848803; COSMIC: COSV99848803; API