16-23626386-AC-A

Variant names:

• chr16-23626386-AC-A
• rs786204156
• NM_024675.4:c.2597delG

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.2597delG​(p.Gly866ValfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G866G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.30
• Publications: 2 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23626386-AC-A is Pathogenic according to our data. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23626386-AC-A is described in CliVar as Pathogenic. Clinvar id is 188219.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.2597delG	p.Gly866ValfsTer5	frameshift_variant	Exon 7 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2597delG	p.Gly866ValfsTer5	frameshift_variant	Exon 7 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Jul 10, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Nov 06, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 1 nucleotide from exon 7 of the PALB2 mRNA (c.2597delG), causing a frameshift at codon 866. This creates a premature translational stop signal (p.Gly866Valfs*5) and is expected to result in an absent or disrupted protein product. While this particular sequence change has not been reported in the literature, truncating sequence changes in PALB2 are known to be pathogenic (PMID: 25099575, 17200668). For these reasons, this sequence change has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs786204156; hg19: chr16-23637707;