rs730881868

Positions:

• chr16-23626338-A-ACAAC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000261584.9(PALB2):​c.2645_2646insGTTG​(p.Cys882TrpfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 ENST00000261584.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.622

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23626338-A-ACAAC is Pathogenic according to our data. Variant chr16-23626338-A-ACAAC is described in ClinVar as [Pathogenic]. Clinvar id is 182741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2645_2646insGTTG	p.Cys882TrpfsTer3	frameshift_variant	7/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2645_2646insGTTG	p.Cys882TrpfsTer3	frameshift_variant	7/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 13, 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	Baylor Genetics	Aug 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2023	ClinVar contains an entry for this variant (Variation ID: 182741). This sequence change creates a premature translational stop signal (p.Cys882Trpfs*3) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2023	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; Published functional studies demonstrate a damaging effect: deficient homologous recombination efficiency and PARP inhibitor resistance (Boonen et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28495237, 26681312, 17200668, 17200671, 17200672, 24136930, 25099575, 34326862, 32090079, 31757951) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 21, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 12, 2022	The c.2642_2645dupGTTG pathogenic mutation, located in coding exon 7 of the PALB2 gene, results from a duplication of GTTG between nucleotide positions 2642-2645, causing a translational frameshift with a predicted alternate stop codon (p.C882Wfs*3). This alteration has been identified in patients with breast cancer, who had NGS hereditary cancer panel testing (Frey MK et al. Gynecol. Oncol. 2017 07;146:123-128; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 15, 2022	This variant inserts 4 nucleotides in exon 7 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. A functional study has reported that this variant results in the loss of PALB2 function in homology-directed repair and resistance to PARP inhibitor assays (PMID: 31757951). This variant has been reported in at least two individuals affected with breast cancer (PMID: 26681312, 28495237). 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. -

PALB2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2024

The PALB2 c.2642_2645dupGTTG variant is predicted to result in a frameshift and premature protein termination (p.Cys882Trpfs*3). This variant was reported in individuals with breast cancer (Supplementary Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S4, Bhai et al. 2021. PubMed ID: 34326862). Functional studies have demonstrated that this variant results in loss of PALB2 homology directed repair and resistance to PARP inhibitor assays (Boonen et al. 2019. PubMed ID: 31757951). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182741/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 30, 2022

Variant summary: PALB2 c.2642_2645dupGTTG (p.Cys882TrpfsX3) 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 was absent in 251490 control chromosomes (gnomAD). c.2642_2645dupGTTG has been reported in the literature in settings of multigene panel testing in individuals with, and in some cases also a family history of, breast cancer (e.g. Susswein_2016, Frey_2017). In a functional study the variant displayed strong defects in homologous recombination, reducing its repair efficiency to approximately 6% of that of wildtype PALB2 (Boonen_2019). Consistent with these findings, cells expressing the variant were also more sensitive than wildtype to treatment with PARP inhibitors (Boonen_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730881868; hg19: chr16-23637659;