chr16-23624004-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP3BP6

The NM_024675.4(PALB2):c.2834+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,565,580 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PALB2
NM_024675.4 splice_region, intron

Scores

Splicing: ADA: 0.9832

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.138

Publications

2 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: 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

PALB2 links:

ENSG00000261723 (HGNC:58305):

ENSG00000261723 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

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

BP6

Variant 16-23624004-C-T is Benign according to our data. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057. Variant chr16-23624004-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 530057.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4 link	c.2834+5G>A		splice_region_variant, intron_variant	Intron 8 of 12	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 link	c.2834+5G>A		splice_region_variant, intron_variant	Intron 8 of 12	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

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:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250218

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000273

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1413274

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705766

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32412

American (AMR)

AF:

0.00

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

85214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1067998

Other (OTH)

AF:

0.00

AC:

AN:

58810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000131

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000162

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:2

Feb 18, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 8 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs570455216, gnomAD 0.03%). This variant has been observed in individual(s) with breast cancer (PMID: 34846068). ClinVar contains an entry for this variant (Variation ID: 530057). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Sep 06, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dec 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a G to A nucleotide substitution at the +5 position of intron 8 of the PALB2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An minigene splicing assay has shown that this variant causes a leaky out-of-frame skipping of exon 8 affecting approximately 60% of transcripts (PMID: 34846068). To our knowledge, this variant has not been reported in individuals affected with PALB2-related disorders in the literature. This variant has been identified in 6/250218 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

PALB2-related disorder

Uncertain:1

Jun 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PALB2 c.2834+5G>A variant is predicted to interfere with splicing. This variant has been reported in an individual with breast cancer (Valenzuela-Palomo et al. 2022. PubMed ID: 34846068). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations of pathogenicity, ranging from likely benign to uncertain, in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/530057/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.59

Splicevardb

3.0

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.71

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over