chr16-23636392-T-G

Position:

• chr16-23636392-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024675.4(PALB2):​c.212-58A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,180,030 control chromosomes in the GnomAD database, including 553 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (62 hom., cov: 32)
  • Exomes 𝑓: 0.029 (491 hom.)
• Consequence: PALB2 NM_024675.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.160

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-23636392-T-G is Benign according to our data. Variant chr16-23636392-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 126635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23636392-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0221 (3360/152190) while in subpopulation NFE AF= 0.0298 (2028/68000). AF 95% confidence interval is 0.0287. There are 62 homozygotes in gnomad4. There are 1641 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 62 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.212-58A>C		intron_variant		ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.212-58A>C		intron_variant		1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3365 AN: 152072 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00592

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0288

GnomAD4 exome AF: 0.0289 AC: 29699 AN: 1027840 Hom.: 491 AF XY: 0.0289 AC XY: 14989 AN XY: 517932

Gnomad4 AFR exome AF: 0.00503

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0358

Gnomad4 EAS exome AF: 0.0000904

Gnomad4 SAS exome AF: 0.0265

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0315

Gnomad4 OTH exome AF: 0.0287

GnomAD4 genome AF: 0.0221 AC: 3360 AN: 152190 Hom.: 62 Cov.: 32 AF XY: 0.0220 AC XY: 1641 AN XY: 74432

Gnomad4 AFR AF: 0.00590

Gnomad4 AMR AF: 0.0253

Gnomad4 ASJ AF: 0.0464

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0298

Gnomad4 OTH AF: 0.0285

Alfa AF: 0.0228 Hom.: 4

Bravo AF: 0.0224

Asia WGS AF: 0.00782 AC: 28 AN: 3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Oct 26, 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

Likely 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	-0.88
CADD	Benign	0.15
DANN	Benign	0.71

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: rs80291632; hg19: chr16-23647713; COSMIC: COSV104552834; COSMIC: COSV104552834;