rs587776416

Positions:

• chr16-23629985-CAT-C

Variant summary

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

The NM_024675.4(PALB2):​c.2167_2168delAT​(p.Met723fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 0.661

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23629985-CAT-C is Pathogenic according to our data. Variant chr16-23629985-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 136132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23629985-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2167_2168delAT	p.Met723fs	frameshift_variant	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2167_2168delAT	p.Met723fs	frameshift_variant	5/13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000636 AC: 16 AN: 251488 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

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: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461892 Hom.: 0 AF XY: 0.0000193 AC XY: 14 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74304

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 19, 2021	This frameshift variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast cancer, ovarian cancer, and pancreatic cancer (PMIDs: 32339256 (2020), 31844177 (2020), 31263054 (2019), 31206626 (2019), 30322717 (2018), 29945567 (2018)). The frequency of this variant in the general population, 0.00035 (12/34592 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	SNPedia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	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; This variant is associated with the following publications: (PMID: 30322717, 29945567, 26689913, 32339256, 32566746, 33193564, 25099575, 24556926, 26270727, 24448499, 26845104, 26315354, 28281021, 28724667, 28453507, 29752822, 27624329, 31206626, 31263054, 31447099, 30613976) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 23, 2019	- -

Familial cancer of breast Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 14, 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	Counsyl	Jan 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Met723Valfs*21) 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 (rs587776416, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 24448499, 24556926, 25099575). ClinVar contains an entry for this variant (Variation ID: 136132). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 14, 2021	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

Hereditary cancer-predisposing syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2022	This variant deletes 2 nucleotides in exon 5 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 20 individuals and families affected with breast and ovarian cancer (PMID: 24448499, 24556926, 26315354, 27624329, 31206626, 32566746). This variant has shown significant association with breast and/or ovarian cancer in the Hispanic population (OR 12.9, 95% CI 3.5 to 51.2) compared to ancestry-matched ExAC control individuals (PMID: 31206626). Haplotype analysis suggests that this may be a founder mutation that arose independently in the Italian and Hispanic populations (PMID: 27624329). This variant has been identified in 16/251488 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	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This frameshifting variant in exon 5 of 13 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple individuals and families diagnosed with breast or ovarian cancer (PMID:24556926, 27624329, 32566746, 26270727, 33193564, 31263054, 26315354, 25099575) and at least one individual with pancreatic cancer (PMID: 29945567). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (16/251488) and thus is presumed to be rare. Based on the available evidence, the c.2167_2168del (p.Met723ValfsTer21) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2022	The c.2167_2168delAT pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of two nucleotides at positions 2167 and 2168, causing a translational frameshift with a predicted alternate stop codon (p.M723Vfs*21). This mutation has previously been reported in multiple individuals diagnosed with breast or ovarian cancer (Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Catucci I et al. Genet. Med. 2014 Sep;16:688-94; Kanchi KL et al. Nat Commun. 2014;5:3156; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51; Sun J et al. Clin. Cancer Res. 2017 Oct 15:23:6113-6119). This mutation has been identified as a founder mutation in Italian, Hispanic and Nigerian populations (Catucci I et al. Cancer Res. Treat. 2016 Nov;160:121-129). 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, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 10-08-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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:3

Pathogenic, criteria provided, single submitter	research	Cancer Genomics Group, Japanese Foundation For Cancer Research	May 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2020	Variant summary: PALB2 c.2167_2168delAT (p.Met723ValfsX21) 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 6.3e-05 in 253056 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer Syndrome (6.3e-05 vs 0.00016), allowing no conclusion about variant significance. c.2167_2168delAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome as well as other cancer types (example: Catucci_2014, Kanchi_2014, Antoniou_2014, Nassar_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2022	The p.Met723fs variant in PALB2 has been reported in at least 9 individuals with hereditary breast cancer and in 1 individual with ovarian cancer (Antoniou 2014, Kanchi 2014, Catucci 2014, Catucci 2016) and segregated with disease in 9 affected relatives (including 2 with other PALB2-associated cancers) from 2 families (Catucci 2016). Additionally, this variant has been identified in 6/11578 of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587776416). The p.Met723fs variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 723 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast cancer in an autosomal dominant manner based upon segregation studies and the predicted impact to the protein. -

Fanconi anemia complementation group N Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 28, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 02, 2023	- -

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

Mar 30, 2022

- -

Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

This sequence change creates a premature translational stop signal (p.Met723Valfs*21) 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 (rs587776416, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 24448499, 24556926, 25099575). ClinVar has an entry for this variant (Variation ID: 136132) with 18 submissions. Therefore, this variant has been classified as Pathogenic. -

Malignant tumor of pancreas Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Mar 03, 2018

- -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Mar 03, 2018

- -

Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1+PS4_Supporting+PP1_Strong -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587776416; hg19: chr16-23641306; COSMIC: COSV55170455;