Variant rs45516100 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024675.4(PALB2):c.3300T>G(p.Thr1100Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,614,080 control chromosomes in the GnomAD database, including 732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 72 hom., cov: 31)

Exomes 𝑓: 0.028 ( 660 hom. )

Consequence

PALB2
NM_024675.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 0.305

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]

PALB2 links:

PALB2 (HGNC:):

PALB2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-23607914-A-C is Benign according to our data. Variant chr16-23607914-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 126730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23607914-A-C is described in Lovd as [Benign]. Variant chr16-23607914-A-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.305 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3300T>G	p.Thr1100Thr	synonymous_variant	12/13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.3300T>G	p.Thr1100Thr	synonymous_variant	12/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

3870

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0173

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.0269

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0299

Gnomad OTH

AF:

0.0321

GnomAD3 exomes

AF:

0.0237

AC:

5950

AN:

251488

Hom.:

104

AF XY:

0.0248

AC XY:

3367

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.0351

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0266

Gnomad FIN exome

AF:

0.0199

Gnomad NFE exome

AF:

0.0293

Gnomad OTH exome

AF:

0.0293

GnomAD4 exome

AF:

0.0279

AC:

40855

AN:

1461824

Hom.:

660

Cov.:

AF XY:

0.0282

AC XY:

20473

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0165

Gnomad4 AMR exome

AF:

0.0175

Gnomad4 ASJ exome

AF:

0.0357

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0258

Gnomad4 FIN exome

AF:

0.0195

Gnomad4 NFE exome

AF:

0.0299

Gnomad4 OTH exome

AF:

0.0281

GnomAD4 genome

AF:

0.0254

AC:

3865

AN:

152256

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1885

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0172

Gnomad4 AMR

AF:

0.0268

Gnomad4 ASJ

AF:

0.0464

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0239

Gnomad4 FIN

AF:

0.0180

Gnomad4 NFE

AF:

0.0299

Gnomad4 OTH

AF:

0.0318

Alfa

AF:

0.0283

Hom.:

Bravo

AF:

0.0260

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0389

EpiControl

AF:

0.0363

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 23, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 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	- -

not provided

Benign:4

Benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 07, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial cancer of breast

Benign:2

Likely benign, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

Fanconi anemia complementation group N

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Breast-ovarian cancer, familial, susceptibility to, 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Thr1100= variant was identified in 196 of 6158 proband chromosomes (frequency: 0.03) from individuals or families with breast cancer, ovarian cancer, or malignant melanoma (Aoude 2014, Erkko 2007, Rahman 2007, Kluska 2017, Catucci 2014). The variant was also identified in ClinVar (classified as benign by Invitae, Ambry Genetics, Prevention Genetics, and three other submitters; and as likely benign by three submitters), LOVD 3.0 (20x as not affecting function), and then Zhejiang Colon Cancer Database (5 entries classified as â€šÃ„Ãºprobably no pathogenicityâ€šÃ„Ã¹). The variant was not identified in Cosmic or the MutDB databases. The variant was identified in control databases in 6664 of 282864 chromosomes (112 homozygous) at a frequency of 0.02, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 363 of 10370 chromosomes (freq: 0.04), European (Non-Finnish) in 3775 of 129186 chromosomes (freq: 0.03), Other in 200 of 7226 chromosomes (freq: 0.03), South Asian in 815 of 30616 chromosomes (freq: 0.03), European (Finnish) in 499 of 25118 chromosomes (freq: 0.02), African in 421 of 24958 chromosomes (freq: 0.02), Latino in 589 of 35440 chromosomes (freq: 0.02), and East Asian in 2 of 19950 chromosomes (freq: 0.0001). The p.Thr1100= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.0

DANN

Benign

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over