rs1555458187

Variant names:

• chr16-23607907-C-CGCTGAGAG
• rs1555458187
• NM_024675.4:c.3299_3306dupCTCTCAGC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.3299_3306dupCTCTCAGC​(p.Val1103LeufsTer6) 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. S1102S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.0100

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]

ENSG00000261723 (HGNC:58305):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23607907-C-CGCTGAGAG is Pathogenic according to our data. Variant chr16-23607907-C-CGCTGAGAG is described in ClinVar as [Pathogenic]. Clinvar id is 460986.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.3299_3306dupCTCTCAGC	p.Val1103LeufsTer6	frameshift_variant	Exon 12 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.3299_3306dupCTCTCAGC	p.Val1103LeufsTer6	frameshift_variant	Exon 12 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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Apr 08, 2020

Center of Medical Genetics and Primary Health Care

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The PALB2 variant p.Val1103Leufs is a frameshift variant in exon 12 located in BRCA1 and RAD51 interaction domain. The duplication causes a frameshift which changes a Valine to a Leucine at codon 1103, and creates a premature stop codon at position 6 of the new reading frame and it is predicted to cause loss of normal protein function through protein truncation and disrupt the regions required for interaction with POLH and POLH DNA synthesis stimulation, Rad51, and BRCA2, as well as the last 3 (WD5-7) WD repeats (PMID: 19609323; 20871615) (PVS1 Pathogenic Very Strong). It is in a mutation hotspot and in a vicinity of 13 pathogenic variants (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign prediction supports its deleterious effect (PP3 Pathogenic Supporting). The variant is reported in ClinVar as a pathogenic variant. In our study this variant was found in a 51-year-old female with a family history of cancer. Therefore, this variant is classified as a Pathogenic. -

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val1103Leufs*6) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 460986). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671, 19609323, 20927582, 21165770). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 15, 2023

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. -

not provided Pathogenic:1

Nov 15, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of eight nucleotides in PALB2 is denoted c.3299_3306dupCTCTCAGC at the cDNA level and p.Val1103LeufsX6 (V1103LfsX6) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ACGA[dupCTCTCAGC]GTGG. The duplication causes a frameshift which changes a Valine to a Leucine at codon 1103, and creates a premature stop codon at position 6 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation. The last 84 correct amino acids are replaced by 5 incorrect ones, disrupting the regions required for interaction with POLH and POLH DNA synthesis stimulation, Rad51, and BRCA2, as well as the last 3 (WD5-7) WD repeats (Oliver 2009, Buisson 2010, Buisson 2014, UniProt). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 26, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3299_3306dupCTCTCAGC pathogenic mutation, located in coding exon 12 of the PALB2 gene, results from a duplication of CTCTCAGC at nucleotide position 3299, causing a translational frameshift with a predicted alternate stop codon (p.V1103Lfs*6). This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 83 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been identified in multiple individuals diagnosed with breast cancer (Weitzel JN et al. Cancer, 2019 08;125:2829-2836; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555458187; hg19: chr16-23619228;