GeneBe

rs587781411

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_024675.4(PALB2):​c.3507_3508delTC​(p.His1170PhefsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PALB2
NM_024675.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19U:1

Conservation

PhyloP100: 1.47
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23603511-TGA-T is Pathogenic according to our data. Variant chr16-23603511-TGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140978.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=11}. Variant chr16-23603511-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PALB2NM_024675.4 linkc.3507_3508delTC p.His1170PhefsTer19 frameshift_variant Exon 13 of 13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkc.3507_3508delTC p.His1170PhefsTer19 frameshift_variant Exon 13 of 13 1 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152006
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461866
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152006
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74220
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:19Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Pathogenic:7
May 18, 2017
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2015
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: case-control

- -

May 13, 2019
Leiden Open Variation Database
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

Jan 14, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change results in a frameshift in the PALB2 gene (p.His1170Phefs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PALB2 protein and extend the protein by 1 additional amino acid residues. This variant is present in population databases (rs587781411, gnomAD 0.1%). This frameshift has been observed in individual(s) with breast, ovarian and prostate cancer and breast cancer (PMID: 24556621, 25099575, 25225577, 26283626, 26314354, 26786923). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3504_3505del. This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Y1183*) have been determined to be pathogenic (PMID: 17200671). 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. -

Mar 31, 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 creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. Functional studies indicate this variant impacts protein function [PMID: 19423707, 19609323]. -

Mar 18, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 28, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PVS1_MOD,PS4,PM2_SUP_MOD,PP1 -

not provided Pathogenic:3
-
SNPedia
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Sep 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 09, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift variant predicted to result in an extension of the protein, as the last 17 amino acids are replaced with 18 different amino acids, which disrupts a portion of the seventh WD repeat and the critical region required for interaction with RAD51, BRCA2, POLH, and POLH DNA synthesis stimulation (PMID: 19609323, 20871615, 24485656); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26283626, 28825143, 17200671, 26314360, 16793542, 19609323, 26315354, 24556621, 25225577, 25099575, 19423707, 19584259, 24998779, 29431189, 29752822, 32339256, 30982232, 34326862, 34439348, 33804961, 28888541, 32125938, 31428676, 26786923, 31841383, 30254378, 34917121, 20871615, 24485656) -

Hereditary breast ovarian cancer syndrome Pathogenic:3
Apr 02, 2025
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

According to the ClinGen ACMG PALB2 v1.1.0 criteria we chose these criteria: PVS1 (strong pathogenic): PVS1 PALB2 descision tree: frameshift - altered region is critical for protein function (frameshift upstream p.His1184), PM2 (supporting pathogenic): gnomAD v4 <= 1/300,000 alleles, PP1 (supporting pathogenic): Hartley 2014, segregation of this alteration with disease in 4 out of 5 individuals from one family -

Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 30, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PALB2 c.3507_3508delTC (p.His1170PhefsX19) causes a frameshift which results in an extension of the protein. The variant was absent in 251472 control chromosomes. c.3507_3508delTC has been reported in the literature in individuals affected with Hereditary Breast Cancer, Colon cancer and other unspecified cancer (Yang_2020), and segregated with disease in a British family with Breast cancer (Hartley _2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.The following publications have been ascertained in the context of this evaluation (PMID: 25225577, 31841383). ClinVar contains an entry for this variant (Variation ID: 140978). Based on the evidence outlined above, the variant was classified as pathogenic. -

Fanconi anemia complementation group N Pathogenic:2
Mar 06, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 09, 2023
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2
Jan 25, 2024
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3507_3508delTC variant, located in coding exon 13 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 3507 to 3508, causing a translational frameshift with a predicted alternate stop codon (p.H1170Ffs*19). This alteration occurs at the 3' terminus of the PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, alters the last 17 amino acids of the protein and results in the elongation of the protein by one amino acid. However, these 3' amino acids are part of the functionally critical WD40 domain that is necessary for PALB2 function, stability, and interaction with BRCA2 (Oliver AW et al. EMBO Rep., 2009 Sep;10:990-6). This alteration has also been reported in multiple individuals with personal and/or family history suggestive of hereditary breast, ovarian, or prostate cancer (Leongamornlert D et al. Br J Cancer. 2014 Mar 18;110(6):1663-72; Hartley T et al. Hered Cancer Clin Pract. 2014 Aug 28;12(1):19; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11); Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Zhang K et al. Breast Cancer Res. Treat. 2017 Dec;166:865-873; Lee JEA et al. J. Pathol. 2018 May;245:53-60; Li JY et al. Int. J. Cancer. 2019 01;144:281-289; Rowley SM et al. Genet. Med., 2019 04;21:913-922; Yadav S et al. J. Clin. Oncol., 2020 May;38:1409-1418). Further, Hartley et al., reported segregation of this alteration with disease in 4 out of 5 individuals from one family. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Dec 07, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant deletes 2 nucleotides in the last coding exon 13 of the PALB2 gene, substituting the last 17 amino acids of the protein with 18 different amino acids. This variant may also be known as c.3504_3505del. The variant impacts the C-terminus of the WD40 repeats domain, a known functional domain (PMID: 16793542, 19423707). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals with personal and/or family history of breast and ovarian cancer (PMID: 25099575, 25225577, 26283626, 26315354, 26786923, 29752822, 29431189, 28825143) and prostate cancer (PMID: 24556621), including one family in which the variant segregates with three first-degree relatives with early-onset or bilateral breast cancer (PMID: 25225577). This variant has been identified in 1/31326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

PALB2-related disorder Pathogenic:1
Mar 05, 2022
DASA
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3507_3508del ;p.(His1170Phefs*?) is a null frameshift variant (NMD) in the PALB2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 140978; 25225577; PMID: 26283626; PMID: 25099575; PMID: 24556621; PMID: 26786923)PS4. The variant is present at low allele frequencies population databases (rs587776428 – gnomAD 0.00006579%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 25225577, 24556621) - PP1_moderate. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1
Jan 22, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Apr 24, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PVS1_STR -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776428; hg19: chr16-23614832; API