rs879254193

Variant names:

• chr16-23622964-C-A
• rs879254193
• NM_024675.4:c.2996+5G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23622964-C-A
• chr16-23622964-C-G
• chr16-23622964-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024675.4(PALB2):​c.2996+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PALB2 NM_024675.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10
• Conservation: PhyloP100: 2.25
• Publications: 1 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: Ambry Genetics
• PALB2-related cancer predisposition

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

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PALB2-AS1 (HGNC:58305):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.2996+5G>T		splice_region intron	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.2936+5G>T		splice_region intron	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.2924+5G>T		splice_region intron	N/A	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.2996+5G>T		splice_region intron	N/A	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2111+5G>T		splice_region intron	N/A	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.3002+5G>T		splice_region intron	N/A	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.0000662 AC: 4 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	Familial cancer of breast (5)
1	2	-	Hereditary cancer-predisposing syndrome (3)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	PALB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.87
PhyloP100		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.50		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879254193; hg19: chr16-23634285;