16-23603471-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_024675.4(PALB2):c.3549C>G(p.Tyr1183Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,612,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y1183Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: PALB2 NM_024675.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22 O:2
• Conservation: PhyloP100: 0.163

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 12 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.
• PP5: Variant 16-23603471-G-C is Pathogenic according to our data. Variant chr16-23603471-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23603471-G-C is described in Lovd as [Pathogenic]. Variant chr16-23603471-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.3549C>G	p.Tyr1183Ter	stop_gained	13/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.3549C>G	p.Tyr1183Ter	stop_gained	13/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251420 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135892

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1459918 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 726432

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: 0.0000513

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

Gnomad4 AFR AF: 0.0000242

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: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 22, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Tyr1183*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the PALB2 protein. This variant is present in population databases (rs118203998, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast, ovarian and pancreatic cancer, and Fanconi anemia (PMID: 17200668, 17200671, 21365267, 22241545, 26315354). ClinVar contains an entry for this variant (Variation ID: 1245). 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 affects PALB2 function (PMID: 17200671, 19609323). For these reasons, this variant has been classified as Pathogenic. -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2019	Variant summary: PALB2 c.3549C>G (p.Tyr1183X) 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. Another truncation at this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251420 control chromosomes. c.3549C>G has been reported in the literature in multiple individuals affected with Breast Cancer as well as Fanconi Anemia (e.g. Antoniou_2014, Susswein_2016, Reid_2007). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 21, 2019	The PALB2 c.3549C>G (p.Tyr1183*) variant causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast/ovarian cancer (PMIDs: 17200668 (2007), 22241545 (2012), 26315354 (2015)), pancreatic cancer (PMID: 21365267 (2011)), and medulloblastoma (PMID: 29753700 (2018)). It has also been observed in two compound heterozygous individuals with Fanconi anemia (PMID: 17200671 (2007)). Functional studies also show this variant causes defective DNA repair and lacks cisplatin resistance (PMID: 31757951 (2019)). The frequency of this variant in the general population, 0.000035 (4/113726 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2022	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: defective homologous recombination (HR) efficiency, reduced resistance to cisplatin and PARP, and increased mitotic index indicating a defective checkpoint (Boonan 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23935381, 19584259, 26845104, 27356891, 17200668, 17200671, 24728327, 22241545, 26898890, 25099575, 24949998, 26681312, 28873162, 19609323, 20927582, 28008555, 26283626, 24415441, 28779002, 29360161, 29753700, 29785153, 30322717, 31159747, 29625052, 32339256, 32546565, 34113003, 33882707, 24485656, 20871615, 31757951) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a single amino acid change from Tyrosine to a Termination codon at amino acid residue 1183 of the PALB2 gene and it is expected to delete the last 4 amino acids of the PALB2 protein. This variant has been reported in individuals affected with breast, ovarian and pancreatic cancer, and Fanconi anemia (PMID: 17200668, 26315354, 17200671, 21365267, 22241545). Experimental studies have shown that this variant prevents closure of the WD40 ring structure and destabilizes the PALB2 protein in cell culture (PMID: 19609323). Truncating variants in PALB2 are known to be pathogenic. The mutation database Clinvar contains entries for this variant (Variation ID: 1245). -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2017	The PALB2 c.3549C>G;p.Tyr1183Ter variant has been described in individuals and families affected with breast cancer and Fanconi anemia (Rahman 2007, Reid 2007, Tischkowitz 2012). This variant removes four amino acids thought to be critical in the protein structure, which may destabilize the protein (Oliver 2009). In support of this theory, cells derived from individuals with this variant do not produce PALB2 protein (Reid 2007). The variant is listed in the ClinVar database (Variation ID: 1245) and the dbSNP variant database (rs118203998) with an allele frequency of 0.001625 percent in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. Pathogenic PALB2 variants increase susceptibility to breast and pancreatic cancer (OMIM#601355). References: Oliver AW et al. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2009 Sep;10(9):990-6. Rahman N et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007 Feb;39(2):165-7. Reid S et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007 Feb;39(2):162-4. Tischkowitz M et al. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat. 2012 Apr;33(4):674-80. -

Hereditary cancer-predisposing syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 13, 2021	- -
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	Sep 29, 2021	The p.Y1183* pathogenic mutation (also known as c.3549C>G), located in coding exon 13 of the PALB2 gene, results from a C to G substitution at nucleotide position 3549. This changes the amino acid from a tyrosine to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last four 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 alteration has been identified in numerous individuals with breast (including triple negative and male breast cancer diagnoses), pancreatic, and ovarian cancers (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Jones S et al. Science. 2009 Apr;324:217; Hofstatter EW et al. Fam. Cancer. 2011 Jun;10:225-31; Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80; Couch FJ et al. J Clin Oncol. 2015 Feb;33:304-11; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Shirts BH et al. Genet Med. 2016 10;18:974-81; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Dudley B et al. Cancer. 2018 Apr;124:1691-1700; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488; Woodward ER et al. Genet Med. 2021 Jun;:). In one study, an individual with clinical features of Fanconi Anemia-N (FA-N) who carried p.Y1183* in conjunction with a PALB2 frameshift mutation was found to have no detectable PALB2 protein in lymphoblastoid cells (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 07, 2023	This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal in the last coding exon. A structural study suggests that this variant interferes with protein folding and may destabilize PALB2 protein (PMID: 19609323), and PALB2 protein was not detectable in cell culture from an individual carrying this variant (PMID: 17200671). A functional study has reported that this variant disrupted PALB2 function in a homology-mediated DNA repair and cisplatin-sensitivity assays (PMID: 31757951). This variant has been reported in more than 44 individuals affected with breast cancer (including bilateral, triple-negative, and male breast cancer), ovarian cancer, pancreatic cancer, and in biallelic carriers affected with Fanconi anemia (PMID: 17200668, 17200671, 20927582, 21365267, 22241545, 24415441, 25099575, 25225577, 25452441, 26283626, 26296701, 26315354, 26641009, 26681312, 26898890, 28008555, 29360161, 31575519, 32012241, 32339256, 32546565, 34113003). In addition, this variant segregated with disease in at least one family (PMID: 21365267). This variant has been identified in 4/251420 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 15, 2022	- -

Fanconi anemia complementation group N Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 14, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2007	- -

Pancreatic cancer, susceptibility to, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PALB2 p.Tyr1183* variant was identified in 11 of 15,266 proband chromosomes (frequency: 0.0007) from individuals or families with Fanconi anemia or ovarian, breast or pancreatic cancer and was not identified in 13,140 control chromosomes from healthy individuals (Reid 2007, Rahman 2007, Ramus 2015, Hofstatter 2011, Tischkowitz 2012, Thompson 2015, Ding 2011). The variant was identified in dbSNP (rs118203998) as “with pathogenic allele, ClinVar (classified as pathogenic by Invitae, Color, GeneDx, Ambry Genetics and 8 other submitters; and as likely pathogenic by Peter MacCallum Cancer Centre) and LOVD 3.0 (observed 13x). The variant was identified in control databases in 4 of 246,208 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 4 of 111,674 chromosomes (freq: 0.00004); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The c.3549C>G variant leads to a premature stop codon at position 1183; this position is 4 residues from the C-terminus of the protein, which is not usually predicted to result in non-sense mediated decay. However, the PALB2 protein was absent in lymphoblastoid cells derived from patients expressing this variant (Reid 2007). Analysis of the PALB2 protein structure likely explains this protein absence as this variant is predicted to destabilize the PALB2 protein by preventing closure of the ring structure, resulting in incomplete protein folding and rapid degradation (Oliver 2009). 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. -

PALB2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 29, 2019

The PALB2 c.3549C>G (p.Tyr1183Ter) variant is a stop-gained variant that is predicted to result in a truncated protein. Across a selection of the available literature, the p.Tyr1183Ter variant has been reported in a heterozygous state in five individuals with familial breast cancer, including in one bilateral and one male case (Rahman et al. 2007; Ding et al. 2011; Tischkowitz et al. 2012). The variant has also been reported in trans with a second null variant in two unrelated individuals with Fanconi anemia (Reid et al. 2007). A different nucleotide change resulting in the same amino acid change has also been reported in a compound heterozygous state in an individual with Fanconi anemia (Reid et al. 2007). The p.Tyr1183Ter variant was absent from 1260 control individuals but is reported at a frequency of 0.000035 in the European (non-Finnish) population of the Genome Aggregation Database. Structural studies based on X-ray crystallography predict that loss of the last four residues of PALB2 caused by p.Tyr1183Ter disrupts the hydrogen bonding in the seventh blade of the beta-propeller, resulting in a misfolded and quickly degraded protein (Oliver et al. 2009). This prediction is consistent with the lack of detectable protein expression found in lymphoblastoid cells from compound heterozygous patients with Fanconi anemia (Reid et al. 2007). Based on the collective evidence, the p.Tyr1183Ter variant is classified as pathogenic for PALB2-related disorders. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Breast cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	30
Dann	Benign	0.97
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.14	N
MutationTaster	Benign	1.0	A
Vest4		0.75
GERP RS		-0.82

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: rs118203998; hg19: chr16-23614792;