Variant rs587781411 details in Genebe, Genetics Data Aggregator

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: {Uncertain_significance=1, Pathogenic=10, Likely_pathogenic=5}. Variant chr16-23603511-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3507_3508delTC	p.His1170fs	frameshift_variant	13/13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.3507_3508delTC	p.His1170fs	frameshift_variant	13/13	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:18Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change results in a frameshift in the PALB2 gene (p.His1170Phefs19). 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. ClinVar contains an entry for this variant (Variation ID: 140978). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 28, 2023	Criteria applied: PVS1_MOD,PS4,PM2_SUP_MOD,PP1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	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]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 18, 2017	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2024	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) -
Pathogenic, no assertion criteria provided	literature only	SNPedia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

Fanconi anemia complementation group N

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 09, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 07, 2020	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2024	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. -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2024	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. -

PALB2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 22, 2024

- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 24, 2024

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.

rs587781411

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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