rs180177133

chr16-23614088-AT-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.3116del(p.Asn1039IlefsTer2) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.0000437 in 1,601,814 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:2
• Conservation: PhyloP100: 4.88

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23614088-AT-A is Pathogenic according to our data. Variant chr16-23614088-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23614088-AT-A is described in Lovd as [Pathogenic]. Variant chr16-23614088-AT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3116del	p.Asn1039IlefsTer2	frameshift_variant, splice_region_variant	11/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3116del	p.Asn1039IlefsTer2	frameshift_variant, splice_region_variant	11/13	1	NM_024675.4	P1
	ENST00000561764.1	n.186-3510del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249950 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135118

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 68 AN: 1449616 Hom.: 0 Cov.: 27 AF XY: 0.0000457 AC XY: 33 AN XY: 722006

Gnomad4 AFR exome AF: 0.0000301

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: 0.0000590

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 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	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Asn1039Ilefs*2) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs180177133, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia, breast cancer, pancreatic cancer, and stomach cancer (PMID: 17200668, 17200671, 19264984, 20412113, 25452441, 26845104). ClinVar contains an entry for this variant (Variation ID: 126715). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Jan 22, 2020	This variant leads to a translational frameshift and the introduction of a premature termination codon at position 2 of the new reading frame. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PALB2 is a well-established mechanism of disease for increased breast cancer risk (Rahman 2007, Janatova 2013, Antoniou 2014). This variant has an allele frequency of 0.00001 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with Fanconi anemia, as well as individuals with breast cancer and pancreatic cancer (Reid 2007, Rahman 2007, Jones 2009, Slater 2010, Couch 2015, Shirts 2016). Thus, this variant is interpreted as pathogenic. PM2; PVS1 -
Likely pathogenic, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2022	This variant changes 1 nucleotide in exon 11 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least 12 individuals affected with breast cancer (PMID: 17200668, 25452441, 26283626, 33471991, 34113003; Leiden Open Variation Database DB-ID PALB2_000014), and two individuals affected with pancreatic, prostate and stomach cancer (PMID: 19264984, 26845104), and in at least 4 unaffected individuals (PMID: 26283626, 33471991; Leiden Open Variation Database DB-ID PALB2_000014). This variant also has been reported in a compound heterozygous carrier with a second PALB2 truncation variation who is affected with Fanconi anemia (PMID: 17200671). This variant has been identified in 3/249950 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	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 13, 2021	The c.3116delA pathogenic mutation, located in coding exon 11 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3116, causing a translational frameshift with a predicted alternate stop codon (p.N1039Ifs*2). This mutation has been reported in individuals affected with familial breast cancer and familial pancreatic cancer (Rahman N et al. Nat. Genet. 2007 Feb;39(2):165-7; Jones S et al. Science 2009 Apr 10;324(5924):217; Slater EP et al. Clin. Genet. 2010 Nov;78(5): 490-4; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Woodward ER et al. Genet Med, 2021 Oct;23:1969-1976; Kondrashova O et al. Cancers (Basel), 2021 04;13; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). It has also been identified in conjunction with another PALB2 mutation in an individual affected with Fanconi anemia type N (Reid S et al. Nat. Genet. 2007 Feb;39(2):162-4). In addition to the clinical data presented in the literature, 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. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2022	Observed in individuals with PALB2-related cancers (Rahman 2007, Jones 2009, Slater 2010, Antoniou 2014, Thompson 2015); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18302019, 20858716, 17200668, 19264984, 20412113, 25099575, 25452441, 26283626, 23935381, 21618343, 21165770, 19763819, 21932393, 23935836, 27595995, 26845104, 28454591, 26786923, 28779002, 29909963, 34113003, 32853339, 32885271, 32581362, 32832836, 31447099, 17200671) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2020	This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, it has been reported in individuals affected with breast cancer (PMID: 17200668 (2007), 25099575 (2014), 25452441 (2015), 26283626 (2015)), pancreatic cancer (PMID: 19264984 (2009), 20412113 (2010)), Fanconi anemia (PMID: 17200671 (2007)), and other cancers (PMID: 29909963 (2018)). Therefore, the variant is classified as pathogenic. -

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 17, 2021

- -

Fanconi anemia complementation group N Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 26, 2021

- -

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.Asn1039IlefsX2 variant was identified in 16 of 15604 proband chromosomes (frequency: 0.001) from individuals or families affected with Fanconi anemia, breast cancer, pancreatic cancer, and stomach cancer and was present in 1 of 3996 control chromosomes (frequency: 0.00025) from healthy individuals (Thompson_2015, Slater_2010, Reid_2007, Rahman_2007, Jones_2009, Zheng_2012, Southey_2013, Couch_2015, Shirts_2016, Antoniou_2014). The variant was also identified in the following databases: dbSNP (ID: rs180177133) as “With Pathogenic allele”, ClinVar and Clinvitae (13x as pathogenic by Ambry Genetics, Invitae, GeneDx, Color Geneomics, Counsyl, PALB2 database, OMIM and as likely pathogenic by Peter MacCallum Cancer Center) and Zhejiang Colon Cancer Database. The variant was not identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 3 of 244820 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). It was observed in the European (Non-Finnish) population in 3 of 110928 chromosomes (freq: 0.000027), but not in other populations. Protein blot analysis of lymphoblastoid cells from individuals with biallelic PALB2 mutations has demonstrated that the mutation results in a null allele confirming its pathogenicity; this study has shown that biallelic pathogenic mutations in PALB2 in affected families cause a new subtype of Fanconi anemia and cancer in early childhood (Reid_2007). The c.3116delA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1039 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 related 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

May 11, 2023

Variant summary: PALB2 c.3116delA (p.Asn1039IlefsX2) 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, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 249950 control chromosomes. c.3116delA has been reported in the literature as a biallelic genotype in at least one individual affected with Fanconi Anemia and childhood cancer and in the heterozygous state in multiple individuals affected with breast cancer (e.g. Reid_2007, Antoniou_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25099575, 17200671). Fifteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=14)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Pancreatic cancer, susceptibility to, 3 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 10, 2009

- -

Breast cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

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: rs180177133; hg19: chr16-23625409;