rs180177135

chr16-23607890-GT-G

Variant summary

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

The NM_024675.4(PALB2):c.3323del(p.Tyr1108SerfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y1108Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 1.12

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 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 49 pathogenic variants in the truncated region.
• PP5: Variant 16-23607890-GT-G is Pathogenic according to our data. Variant chr16-23607890-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 126734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23607890-GT-G is described in Lovd as [Pathogenic]. Variant chr16-23607890-GT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3323del	p.Tyr1108SerfsTer16	frameshift_variant	12/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3323del	p.Tyr1108SerfsTer16	frameshift_variant	12/13	1	NM_024675.4	P1
	ENST00000561764.1	n.185+508del		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000896

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74296

Gnomad4 AFR AF: 0.0000724

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 12, 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	New York Genome Center	Jun 12, 2023	The c.3323del variant identified in PALB2 has previously been reported in the parent of an individual with Fanconi anemia type N (PMID: 17200671), and in multiple individuals with hereditary breast cancer [PMID: 25099575, 25452441, 32427313, 32885271]. The c.3323del variant has been deposited in ClinVar [ClinVar ID: 126734] as Pathogenic by multiple submitters. This variant is observed in 8 alleles in population databases (~0.002% MAF with 0 homozygote in gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.3323del variant, located in exon 12 of this 13-exon gene, is predicted to result in a frameshift variant with premature incorporation of a termination codon (p.Tyr1108SerfsTer16). While this alteration is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5% of the PALB2 protein (79 amino acids). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic [PMID: 17200668, 19609323, 21365267, 22241545, 26315354]. Based on available evidence this c.3323del, p.(Y1108SfsTer16) variant identified in PALB2 is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change creates a premature translational stop signal (p.Tyr1108Serfs*16) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and Fanconi anemia (PMID: 17200671, 25452441, 26845104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 126734). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal does not substantially affect PALB2 function (PMID: 23341105). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200668, 17200671, 19609323, 21365267, 22241545, 26315354). 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	Counsyl	Nov 08, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2021	The c.3323delA pathogenic mutation, located in coding exon 12 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3323, causing a translational frameshift with a predicted alternate stop codon (p.Y1108Sfs*16). This alteration occurs at the 3' terminus of thePALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 5% 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 was reported in a parent of an individual with Fanconi anemia type N (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). This mutation has also been reported in multiple individuals with hereditary breast cancer (Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Shirts BH et al. Genet. Med. 2016 Oct;18:974-81; Crawford B et al. Breast Cancer Res. Treat. 2017 Jun;163(2):383-390; Palmer JR et al. J Natl Cancer Inst. 2020 12;112:1213-1221; Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 Mar;147:871-879). 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). Other truncating alterations downstream have been observed in individuals with a personal and/or family history that is consistent with PALB2-related disease (Ambry internal data). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2022	This variant deletes 1 nucleotide in exon 12 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 individuals affected with breast cancer (PMID: 17200671, 25099575, 25452441, 26845104, 28281021). This variant has not been identified 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	curation	Sema4, Sema4	Aug 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

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	Apr 20, 2022	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21165770, 25452441, 28281021, 23341105, 25263539, 26556299, 2985019, 26845104, 25099575, 28152038, 28873162, 33646313, 32885271, 32427313, 31636395, 17200671) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2023	This frameshift variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with breast cancer (PMIDs: 25452441 (2015), 26845104 (2016), 32427313 (2020), and 32885271 (2021)). A functional study found that this variant was deficient in homology-directed DNA repair activity (PMID: 31636395 (2020)). Based on the available information, this 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 12, 2021

- -

Fanconi anemia complementation group N Pathogenic:1

Pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Jun 28, 2018

ACMG codes: PVS1, PM2, PM3, PP5 -

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.Tyr1108Serfs*16 variant was identified in 5 of 7044 proband chromosomes (frequency: 0.0007) from individuals or families with fanconi anemia and hereditary breast and ovarian cancer (Reid 2007, Couch 2015, Shirts 2016, Antoniou 2014). The variant was identified in dbSNP (rs180177135) as “with pathogenic allele”, ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Counsyl and 4 other submitters) and LOVD 3.0 (observed 5x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3323del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1108 and leads to a premature stop codon at position 1123. 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 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

Apr 16, 2022

Variant summary: PALB2 c.3323delA (p.Tyr1108SerfsX16) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Tyr1183X). The variant was absent in 251818 control chromosomes. c.3323delA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Antoniou_2014, Couch_2016, Crawford_2017, Reid_2007). These data indicate that the variant is likely to be associated with disease. Multiple clinical diagnostic laboratories and the LOVD database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. 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)		0.040		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: rs180177135; hg19: chr16-23619211;