rs876659463

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3PP3PP5_Very_Strong

The NM_024675.4(PALB2):c.3113+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000816 in 1,594,088 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000275968: RNA studies have demonstrated this alteration results in abnormal splicing (Ambry internal data" and additional evidence is available in ClinVar. The gene PALB2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

PALB2
NM_024675.4 splice_region, intron

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.74

Publications

8 publications found

Variant links:

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 links:

PALB2-AS1 (HGNC:58305):

PALB2-AS1 links:

Genome browser will be placed here

ACMG classification

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000275968: RNA studies have demonstrated this alteration results in abnormal splicing (Ambry internal data; Lopez-Perolio I et al. J. Med. Genet. 2019 Jul;56:453-460).; SCV000903684: RNA studies have shown that this variant causes skipping of exon 9 and 10 (PMID: 17200671), deletion of the last 31 nucleotides of exon 10 (PMID: 30890586, 34846068), or skipping of exon 10 (PMID: 32133419) in the RNA transcripts. These aberrant transcripts are expected to result in an absent protein product or disrupted the functionally important WD40 repeats in the PALB2 protein. In a mini-gene assay, only 4.9% of the transcripts produced from the mutant allele showed normal length (PMID: 34846068).; SCV000290864: Studies have shown that this variant results in skipping of exons 9 and 10 or activation of a cryptic splice site in exon 10, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 17200671, 30890586; internal data).; SCV004043219: mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 30890586, 32133419, Myriad internal data].; SCV000322190: Published RNA studies demonstrate aberrant splicing resulting in a predicted null allele in the majority of transcripts (PMID: 30890586, 31642931, 32133419, 34846068); SCV005623211: Assessment of experimental evidence suggests this variant results in abnormal RNA splicing (PMID: 31642931 (2019), 30890586 (2019), 32133419 (2020), 34846068 (2022)).; SCV005877723: "In addition, a minigene assay demonstrated that the mutant allele only produced minimal amounts of wild type length transcript (Valenzuela-Palomo 2022)." PMID: 34846068

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 16-23621357-C-G is Pathogenic according to our data. Variant chr16-23621357-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 231961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PALB2	NM_024675.4	MANE Select	c.3113+5G>C	splice_region intron	N/A	NP_078951.2
PALB2	NM_001407296.1		c.3053+5G>C	splice_region intron	N/A	NP_001394225.1
PALB2	NM_001407297.1		c.3041+5G>C	splice_region intron	N/A	NP_001394226.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3113+5G>C	splice_region intron	N/A	ENSP00000261584.4	Q86YC2
PALB2	ENST00000568219.5	TSL:1	c.2228+5G>C	splice_region intron	N/A	ENSP00000454703.2	H3BN63
PALB2	ENST00000561514.3	TSL:5	c.3119+5G>C	splice_region intron	N/A	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000832

AC:

AN:

1441898

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718778

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33014

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.00

AC:

AN:

85852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

1093936

Other (OTH)

AF:

0.00

AC:

AN:

59766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Familial cancer of breast (3)

Hereditary cancer-predisposing syndrome (2)

Breast-ovarian cancer, familial, susceptibility to, 5 (1)

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Benign

0.95

PhyloP100

4.7

PromoterAI

0.0026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

Splicevardb

3.0

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: 36

DS_DL_spliceai

0.46

Position offset: 5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over