16-23634953-CAA-CA

Position:

• chr16-23634953-CAA-CA

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM5_Supporting PVS1 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1592del (p.L531Cfs*30) variant in PALB2 is a frameshift variant observed to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [HR 6.1 (95% CI 2.2-17.2, p = 0.01)] (PMID:18628482). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. The variant has been reported to segregate with breast cancer in 6 affected family members from three families (Ambry Genetics and Invitae). The minor allele frequency in gnomAD v2.1.1 is 0.001871 in the Finnish population; however, this variant known to be a Finnish founder mutation thus explaining the higher than expected population frequency (PM2_Supporting, BS1, and BA1 are not met; PMID:17287723). In summary, this variant meets criteria to be classified as 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, PS4, PP1_Strong, PM5_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA250432/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:15 O:1
• Conservation: PhyloP100: 2.19

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]

PALB2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1592delT	p.Leu531fs	frameshift_variant	4/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1592delT	p.Leu531fs	frameshift_variant	4/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152098 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: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251486 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135918

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: 0.00203

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 727242

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: 0.00174

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74290

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: 0.00179

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:7

Pathogenic, no assertion criteria provided	research	Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Peradeniya	Oct 19, 2019	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Apr 05, 2023	The c.1592del (p.L531Cfs*30) variant in PALB2 is a frameshift variant observed to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [HR 6.1 (95% CI 2.2-17.2, p = 0.01)] (PMID: 18628482). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*) as classified by the HBOP VCEP, and is expected to be more deleterious. The variant has been reported to segregate with breast cancer in 6 affected family members from three families (Ambry Genetics and Invitae). The minor allele frequency in gnomAD v2.1.1 is 0.001871 in the Finnish population; however, this variant known to be a Finnish founder mutation thus explaining the higher than expected population frequency (PM2_Supporting, BS1, and BA1 are not met; PMID: 17287723). In summary, this variant meets criteria to be classified as 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, PS4, PP1_Strong, PM5_Supporting) -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Leu531Cysfs*30) 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 (rs180177102, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 17287723, 18628482, 19383810, 22241545). It is commonly reported in individuals of Finnish ancestry (PMID: 17287723, 18628482, 19383810, 22241545). ClinVar contains an entry for this variant (Variation ID: 126609). 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: 17287723, 24153426, 26640152). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 04, 2017	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2023	The PALB2 c.1592del (p.Leu531Cysfs*30) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 35610400 (2022), 32546565 (2021), 30322717 (2018), 28724667 (2017), 27631815 (2017), 18628482 (2008)), and it has been characterized as a founder variant in the Finnish population (PMID: 17287723 (2007)). Experimental studies indicate this variant has deleterious effects on PALB2 protein function (PMIDs: 33964450 (2021), 17287723 (2007)). ClinVar contains an entry for this variant (URL: www.ncbi.nlm.nih.gov/clinvar, Variation ID: 126609). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2022	Observed in individuals with breast, ovarian, and prostate cancer and is considered to be a Finnish pathogenic founder variant, present in about 1% of the population (Erkko et al., 2007; Erkko et al., 2008; Heikkinen et al., 2009; Haanpaa et al., 2013; Nikkil et al., 2013; Sokolenko et al., 2015; Kotsopoulos et al., 2017; Kwong et al., 2020; Darst et al., 2021); Published functional studies demonstrate a damaging effect with regards to: DNA binding ability, homologous recombination, crosslink repair, and double stranded break repair (Erkko et al., 2007; Obermeier et al., 2015; Pauty et al., 2017; Boonen et al., 2019; Brnich et al., 2021); Case control studies suggest this variant is associated with breast cancer (Erkko et al., 2007; Erkko et al., 2008; Heikkinen et al., 2009; Southey et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26681312, 27631815, 22241545, 29922827, 24153426, 17287723, 18628482, 25619955, 25959805, 19383810, 26640152, 20003494, 28158555, 28194609, 27783279, 23941127, 28724667, 27099641, 30322717, 32546565, 33964450, 31757951, 32068069, 32853339, 32997802) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 19, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2024	The c.1592delT (p.L531Cfs*30) alteration, located in exon 4 (coding exon 4) of the PALB2 gene, consists of a deletion of one nucleotide at position 1592, causing a translational frameshift with a predicted alternate stop codon after 30 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.017% (49/282888) total alleles studied. The highest observed frequency was 0.187% (47/25120) of European (Finnish) alleles. This mutation is known as a Finnish founder mutation (Erkko, 2007). One study estimated the risk of breast cancer by age 70 for females carriers of this mutation to be 40%, (95% CI, 17-77) (Erkko, 2008). Another study found that c.1592delT was associated with a significant increased risk for breast cancer (OR 3.44) but not with increased risk for prostate or ovarian cancer (Southey, 2016). In another study, this mutation was associated with an aggressive breast tumor phenotype compared to tumors of sporadic or familial breast cancer patients who did not carry the mutation (Heikkinen, 2009). Additional studies have detected this mutation in 3/1824 patients with triple negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch, 2015), in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun, 2017), in 44/154 breast cancer families (Antoniou, 2014), and in 1/1421 epithelial ovarian cancer patients and 0/4300 European controls (Kotsopoulos, 2017). Two studies utilizing lymphoblastoid cell lines showed that this mutation causes aberrant DNA damage response (Nikkilä, 2013; Obermeier, 2016). Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 29, 2023	This variant deletes 1 nucleotide in exon 4 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. Functional studies have shown that this variant has reduced DNA binding, protein instability, and fails to complement PALB2-deficient cells (PMID: 17287723, 24153426, 28158555). This variant has been reported in individuals affected with breast cancer (PMID: 17287723, 18628482,22241545, 23941127, 25452441, 28724667, 27595995). This variant has been identified in 49/282888 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	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

BRCAlab, Lund University

Aug 26, 2022

- -

Breast cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 15, 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: rs180177102; hg19: chr16-23646274;