rs515726067

Positions:

• chr16-23635228-AC-A
• chr16-23635228-AC-ACC

Variant summary

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

The NM_024675.4(PALB2):​c.1317del​(p.Phe440LeufsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,766 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: -0.676

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23635228-AC-A is Pathogenic according to our data. Variant chr16-23635228-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 126598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635228-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1317del	p.Phe440LeufsTer12	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.1317del	p.Phe440LeufsTer12	frameshift_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151934 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: 0.00000400 AC: 1 AN: 249846 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135522

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727218

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151934 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74220

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

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:6

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	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Phe440Leufs*12) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 20852946, 25186627, 25619955, 26681312). This variant is also known as 1517delG. ClinVar contains an entry for this variant (Variation ID: 126598). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 08, 2023	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2021	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 (Lek 2016); This variant is associated with the following publications: (PMID: 28724667, 28779002, 23935381, 21165770, 25619955, 25186627, 20852946, 24870022, 27631815, 26681312, 28152038, 31263054, 32339256) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 26, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2022	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. This variant has been reported in at least 10 individuals affected with breast cancer (PMID: 20852946, 25186627, 25619955, 26681312, 28724667, 31768816, 33471991; Leiden Open Variation Database DB-ID PALB2_010070; Color internal data). This variant has been identified in 1/249846 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	Ambry Genetics	Jun 13, 2022	The c.1317delG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at position 1317, causing a translational frameshift with a predicted alternate stop codon (p.F440Lfs*12). This mutation has been reported in multiple families with histories of early onset breast cancer and melanoma (Balia C et al. Fam. Cancer. 2010 Dec;9:531-6; Sokolenko AP et al. Cancer Lett. 2015 Apr;359:259-61) as well as in several large cohort studies of breast cancer patients undergoing multigene panel testing (Decker B et al. J. Med. Genet. 2017 11;54(11):732-741; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Susswein LR et al. Genet. Med. 2016 08;18(8):823-32; Tung N et al. Cancer 2015 Jan;121(1):25-33) . Of note, this alteration is also designated as c.1517delG by Balia et al. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical information 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2021	Variant summary: PALB2 c.1317delG (p.Phe440LeufsX12) 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. The variant allele was found at a frequency of 4e-06 in 249846 control chromosomes. c.1317delG has been reported in the literature in several individuals and in at least one family affected with Hereditary Breast and Ovarian Cancer (e.g. Balia 2010, Tung 2015, Sokolenko 2015, Susswein 2015, Sun 2017). These data indicate that the variant is very likely to be associated with disease. One study noted that the there was a differential expression of the WT and the mutated mRNA, presumably due to nonsense mediated decay (NMD), though no experimental data was provided (Balia 2010). Seven clinical diagnostic laboratories and one database (LOVD) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Some submitters cite overlapping evidence utilized in the context of this evaluation. 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)		0.010		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: rs515726067; hg19: chr16-23646549;