rs249935

Variant names:

• chr16-23613903-T-C
• rs249935
• NM_024675.4:c.3201+101A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024675.4(PALB2):​c.3201+101A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 829,980 control chromosomes in the GnomAD database, including 5,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1533 hom., cov: 32)
  • Exomes 𝑓: 0.10 (3959 hom.)
• Consequence: PALB2 NM_024675.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000261723 (HGNC:58305):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-23613903-T-C is Benign according to our data. Variant chr16-23613903-T-C is described in ClinVar as Benign. ClinVar VariationId is 1292399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.3201+101A>G		intron_variant	Intron 11 of 12	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3201+101A>G		intron_variant	Intron 11 of 12	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19558 AN: 152010 Hom.: 1522 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0984

Gnomad ASJ AF: 0.0905

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0928

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0883

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.0998 AC: 67645 AN: 677852 Hom.: 3959 AF XY: 0.0994 AC XY: 35470 AN XY: 356678

African (AFR) AF: 0.216 AC: 3777 AN: 17446

American (AMR) AF: 0.0843 AC: 2633 AN: 31246

Ashkenazi Jewish (ASJ) AF: 0.0771 AC: 1546 AN: 20064

East Asian (EAS) AF: 0.193 AC: 6319 AN: 32794

South Asian (SAS) AF: 0.104 AC: 6371 AN: 61374

European-Finnish (FIN) AF: 0.0927 AC: 4402 AN: 47494

Middle Eastern (MID) AF: 0.132 AC: 558 AN: 4228

European-Non Finnish (NFE) AF: 0.0891 AC: 38212 AN: 428940

Other (OTH) AF: 0.112 AC: 3827 AN: 34266

GnomAD4 genome AF: 0.129 AC: 19606 AN: 152128 Hom.: 1533 Cov.: 32 AF XY: 0.129 AC XY: 9584 AN XY: 74394

African (AFR) AF: 0.216 AC: 8941 AN: 41484

American (AMR) AF: 0.0981 AC: 1499 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0905 AC: 314 AN: 3470

East Asian (EAS) AF: 0.173 AC: 897 AN: 5178

South Asian (SAS) AF: 0.103 AC: 495 AN: 4816

European-Finnish (FIN) AF: 0.0928 AC: 984 AN: 10604

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.0883 AC: 6002 AN: 67996

Other (OTH) AF: 0.127 AC: 267 AN: 2102

Alfa AF: 0.113 Hom.: 152

Bravo AF: 0.135

Asia WGS AF: 0.148 AC: 515 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.30
DANN	Benign	0.27
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs249935; hg19: chr16-23625224; COSMIC: COSV55163493;