rs515726081

Variant names:

• chr16-23630007-TTA-T
• rs515726081
• NM_024675.4:c.2145_2146delTA

Variant summary

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

The NM_024675.4(PALB2):​c.2145_2146delTA​(p.Asp715GlufsTer2) 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 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.516

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 16-23630007-TTA-T is Pathogenic according to our data. Variant chr16-23630007-TTA-T is described in ClinVar as [Pathogenic]. Clinvar id is 126638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630007-TTA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2145_2146delTA	p.Asp715GlufsTer2	frameshift_variant	Exon 5 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2145_2146delTA	p.Asp715GlufsTer2	frameshift_variant	Exon 5 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Sep 12, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asp715Glufs*2) 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 hereditary breast and/or ovarian cancer (PMID: 21618343). ClinVar contains an entry for this variant (Variation ID: 126638). For these reasons, this variant has been classified as Pathogenic. -

May 13, 2019

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz. -

PALB2-related disorder Pathogenic:1

Nov 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PALB2 c.2145_2146delTA variant is predicted to result in a frameshift and premature protein termination (p.Asp715Glufs*2). This variant was reported in an individual with breast cancer (Hellebrand et al. 2011. PubMed ID: 21618343). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126638/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

May 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 study demonstrates impaired homology-directed repair activity (Wiltshire et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with a personal and family history of breast cancer (Hellebrand et al., 2011); 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: 24136930, 17200668, 17200671, 17200672, 21618343, 25099575, 31636395) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2145_2146delTA pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 2145 to 2146, causing a translational frameshift with a predicted alternate stop codon (p.D715Efs*2). This alteration was reported in a patient with a personal history of hormone receptor positive breast cancer diagnosed at age 44 and a family history of breast and ovarian cancer (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This alteration was found to be functionally abnormal in a homology-directed DNA repair (HDR) assay (Hellebrand H et al. Hum Mutat, 2011 Jun;32:E2176-88). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs515726081; hg19: chr16-23641328;