chr16-23624007-A-T

Variant names:

• chr16-23624007-A-T
• rs864622481
• NM_024675.4:c.2834+2T>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.2834+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.59
• 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: 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23624007-A-T is Pathogenic according to our data. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23624007-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 2673834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2834+2T>A		splice_donor_variant, intron_variant	Intron 8 of 12	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Jan 27, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 11, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2834+2T>A intronic variant results from a T to A substitution two nucleotides after coding exon 8 of the PALB2 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.6
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 2

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

Other links and lift over

dbSNP: rs864622481; hg19: chr16-23635328;