rs515726081

Positions:

• chr16-23630007-TTA-T

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_2146del​(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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic/Likely 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 [Likely_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/exons	MANE	UniProt
PALB2	NM_024675.4	c.2145_2146del	p.Asp715GlufsTer2	frameshift_variant	5/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2145_2146del	p.Asp715GlufsTer2	frameshift_variant	5/13	1	NM_024675.4	P1

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/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2023	ClinVar contains an entry for this variant (Variation ID: 126638). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 21618343). This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 12, 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. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz. -

PALB2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 08, 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 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2022

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;