rs8053188

chr16-23641204-C-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.-47G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,599,550 control chromosomes in the GnomAD database, including 1,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (308 hom., cov: 32)
  • Exomes 𝑓: 0.026 (857 hom.)
• Consequence: PALB2 NM_024675.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.02

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=-0.64).
• BP6: Variant 16-23641204-C-T is Benign according to our data. Variant chr16-23641204-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 126578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23641204-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.-47G>A		5_prime_UTR_variant	1/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.-47G>A		5_prime_UTR_variant	1/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.0495 AC: 7528 AN: 152210 Hom.: 298 Cov.: 32

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0797

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.0536

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0401 AC: 8852 AN: 220560 Hom.: 288 AF XY: 0.0381 AC XY: 4601 AN XY: 120606

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.0821

Gnomad ASJ exome AF: 0.0545

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.0563

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0368

GnomAD4 exome AF: 0.0262 AC: 37889 AN: 1447222 Hom.: 857 Cov.: 30 AF XY: 0.0267 AC XY: 19204 AN XY: 718822

Gnomad4 AFR exome AF: 0.0972

Gnomad4 AMR exome AF: 0.0850

Gnomad4 ASJ exome AF: 0.0533

Gnomad4 EAS exome AF: 0.00846

Gnomad4 SAS exome AF: 0.0529

Gnomad4 FIN exome AF: 0.0238

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0497 AC: 7574 AN: 152328 Hom.: 308 Cov.: 32 AF XY: 0.0506 AC XY: 3769 AN XY: 74506

Gnomad4 AFR AF: 0.0981

Gnomad4 AMR AF: 0.0801

Gnomad4 ASJ AF: 0.0481

Gnomad4 EAS AF: 0.00869

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0487

Alfa AF: 0.0365 Hom.: 35

Bravo AF: 0.0532

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely 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	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	-	- -

Fanconi anemia complementation group N Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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	-0.64
Cadd	Benign	12
Dann	Benign	0.89

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

Other links and lift over

dbSNP: rs8053188; hg19: chr16-23652525; COSMIC: COSV55166576; COSMIC: COSV55166576;