rs249954

chr16-23629146-G-Achr16-23629146-G-Cchr16-23629146-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024675.4(PALB2):c.2586+58C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,332,896 control chromosomes in the GnomAD database, including 48,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7873 hom., cov: 32)
  • Exomes 𝑓: 0.26 (40877 hom.)
• Consequence: PALB2 NM_024675.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.329

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-23629146-G-A is Benign according to our data. Variant chr16-23629146-G-A is described in ClinVar as [Benign]. Clinvar id is 126663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629146-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2586+58C>T		intron_variant		ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2586+58C>T		intron_variant		1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47107 AN: 151840 Hom.: 7832 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.297

GnomAD4 exome AF: 0.259 AC: 305341 AN: 1180936 Hom.: 40877 AF XY: 0.260 AC XY: 156052 AN XY: 601128

Gnomad4 AFR exome AF: 0.444

Gnomad4 AMR exome AF: 0.276

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.382

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.311 AC: 47213 AN: 151960 Hom.: 7873 Cov.: 32 AF XY: 0.314 AC XY: 23300 AN XY: 74284

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.304

Alfa AF: 0.253 Hom.: 6566

Bravo AF: 0.315

Asia WGS AF: 0.352 AC: 1225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Familial cancer of breast Benign:1

Benign, no assertion criteria provided

curation

Leiden Open Variation Database

May 13, 2019

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

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	-0.90
Cadd	Benign	2.3
Dann	Benign	0.52

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

Other links and lift over

dbSNP: rs249954; hg19: chr16-23640467; COSMIC: COSV55164558;