rs515726117

chr16-23603657-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_024675.4(PALB2):c.3362del(p.Gly1121ValfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000806 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 4.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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 39 pathogenic variants in the truncated region.
• PP5: Variant 16-23603657-AC-A is Pathogenic according to our data. Variant chr16-23603657-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126739.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-23603657-AC-A is described in Lovd as [Pathogenic]. Variant chr16-23603657-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3362del	p.Gly1121ValfsTer3	frameshift_variant	13/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3362del	p.Gly1121ValfsTer3	frameshift_variant	13/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251320 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151828 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74118

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:9

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 23, 2022	PVS1, PS3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Gly1121Valfs*3) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the PALB2 protein. This variant is present in population databases (rs515726117, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 23935836, 24136930, 24549055, 25099575, 26283626; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126739). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Leu1143Thrfs*14 and p.Tyr1183*) have been determined to be pathogenic (PMID: 17200668, 17200671, 21365267, 25099575, 25452441, 26315354; Invitae). 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. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.3362del (p.Gly1121fs) variant in PALB2 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay; however, it is a truncation of a functionally important region (removes amino acids 1123-1187) in a gene where loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminal pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000003979 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1, PM5_Supporting) -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2022	The p.Gly1121ValfsX3 variant in PALB2 has been reported in at least 8 individuals with breast cancer, including 2 siblings with a family history of PALB2-associated cancers (Blanco 2013 PMID: 23935836, Janatova 2013 PMID: 24136930, Castera 2014 PMID: 24549055, Antoniou 2014 PMID: 25099575, Thompson 2015 PMID: 26283626, Couch 2015 PMID: 25452441, Lee 2018 PMID: 29431189) and has also been reported by other clinical laboratories in ClinVar (Variation ID 126739). It was identified in 0.001% (1/67996) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1121 and leads to a premature termination codon 3 amino acids downstream. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~5% of the coding region, with 62 amino acids removed. However, these terminal amino acids are part of the functionally critical WD40 domain that is necessary for PALB2 function, stability, and interaction with BRCA2 (Oliver 2009 PMID: 19609323). In addition, several downstream truncating variants, have been observed in individuals with PALB2-related cancers and Fanconi anemia, supporting the functional importance of the last exon. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant PALB2-associated breast cancer. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PVS1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 15, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	Published functional studies demonstrate a damaging effect: significantly reduced homology directed DNA repair functionality (Wiltshire et al., 2020); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24870022, 29280214, 29431189, 29922827, 24136930, 25452441, 25099575, 24549055, 26283626, 28454591, 31447099, 32338768, 32853339, 34399810, 33804961, 23935836, 31636395) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 08, 2020	DNA sequence analysis of the PALB2 gene demonstrated a single base pair deletion in exon 13, c.3362del. This sequence change is predicted to result in an amino acid frameshift and the creation of a premature stop codon 2 amino acids downstream of the mutation, p.Gly1121Valfs*3. Although this sequence change is located in the last exon of the PALB2 gene, another truncating variant downstream of the p.Gly1121Valfs*3 change, p.Tyr1183*, has been described in individuals with PALB2-related disorders and has been classified as pathogenic (PMID: 17200668, 17200671, 21365267, 25099575, 25452441, 26315354). The p.Gly1121Valfs*3 change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PALB2 protein with potentially abnormal function. This sequence change has been described in the gnomAD database in one individual with an overall population frequency of 0.0004% (dbSNP rs515726117). The p.Gly1121Valfs*3 change has been described in several individuals with breast cancer (PMIDs: 23935836, 26283626, 24136930, 24549055, 25099575, 26283626). This sequence change is located in the WD40-repeat domain of the PALB2 protein, which is known to be involved in binding with BRCA2 (PMIDs: 16793542, 19423707). These collective evidences suggest that this sequence change is pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	This variant deletes 1 nucleotide in exon 13 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least eight individuals affected with breast, ovarian and pancreatic cancer (PMID: 23935836, 24136930, 24549055, 25452441, 29431189, Color internal data). This variant has been identified in 1/251320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 24, 2022	The c.3362delG pathogenic mutation, located in coding exon 13 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3362, causing a translational frameshift with a predicted alternate stop codon (p.G1121Vfs*3). This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 66 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 mutation has been previously reported in numerous kindreds characterized by early-onset breast cancer, triple negative breast cancer, prostate and/or pancreatic cancer (Blanco A at al. PLoS ONE. 2013 Jul;8:e67538; Janatova M et al. Cancer Epidemiol. Biomarkers Prev. 2013 Dec;22:2323-32; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Thompson ER et al. J Clin Oncol, 2016 May;34:1455-9; Lee JEA et al. J. Pathol. 2018 May;245(1):53-60; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). This alteration was found to be functionally abnormal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 30, 2020

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Gly1121Valfs*3 variant was identified in 7 of 9236 proband chromosomes (frequency: 0.0008) from individuals or families with hereditary breast and ovarian cancer or pancreatic cancer (Antoniou 2014, Blanco 2013, Castera 2014, Couch 2015, Thompson 2015, Janatova 2013, Johns 2017). The variant was identified in dbSNP (ID: rs515726117 as “With Pathogenic allele”), ClinVar (5x as pathogenic by Ambry Genetics, Invitae, GeneDx, Color Genomics and PALB2 database and 1x as likely pathogenic by Peter MacCallum Cancer Centre), and LOVD 3.0 Database (5x). The variant was not identified in Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 1 of 246142 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 1 of 111636 chromosomes (freq: 0.000009), but not in the other populations. The p.Gly1121Valfs*3 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1121 and leads to a premature stop codon at position 1123. This alteration is predicted to result in a truncated protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 25, 2019

Variant summary: PALB2 c.3362delG (p.Gly1121ValfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay or disruption of a domain important for PALB2 protein function, which are commonly known mechanisms for disease. The variant disrupts the Partner and localiser of BRCA2, WD40 domain which is involved in BRCA2 binding. A truncations downstream of this position has been classified as pathogenic by our laboratory (eg. p.Tyr1183X). The variant allele was found at a frequency of 4.1e-06 in 246142 control chromosomes. c.3362delG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Blanco_2013, Couch_2016, Janatova_2013, Thompson_2015). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

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: rs515726117; hg19: chr16-23614978;