16-23635382-AG-AGG

Position:

• chr16-23635382-AG-AGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.1163dupC​(p.Leu389fs) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.79

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 16-23635382-A-AG is Pathogenic according to our data. Variant chr16-23635382-A-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 422680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1163dupC	p.Leu389fs	frameshift_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1163dupC	p.Leu389fs	frameshift_variant	4/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 08, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2017	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has not been reported in the literature in individuals with PALB2-related disease. ClinVar contains an entry for this variant (Variation ID: 422680). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu389Serfs*12) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2016

This duplication of one nucleotide in PALB2 is denoted c.1163dupC at the cDNA level and p.Leu389SerfsX12 (L389SfsX12) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCTC[dupC]TCTT. The duplication causes a frameshift which changes a Leucine to a Serine at codon 389, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although PALB2 c.1163dupC has not, to our knowledge, been published in the literature as a germline variant, it was identified in a bone marrow sample from an individual with a personal history of bone marrow failure (Zhang 2015). Based on the currently available information, we consider this duplication to be a likely pathogenic variant. -

Malignant tumor of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 07, 2023

Variant summary: PALB2 c.1163dupC (p.Leu389SerfsX12) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251058 control chromosomes (gnomAD). c.1163dupC has not been reported in the literature in individuals affected with PALB2-related disorders, but has been reported in a bone marrow sample from an individual with bone marrow failure (Zhang_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25239263). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2021

The c.1163dupC pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a duplication of C at nucleotide position 1163, causing a translational frameshift with a predicted alternate stop codon (p.L389Sfs*12). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312772; hg19: chr16-23646703;