rs587776414

Positions:

• chr16-23634945-GAAGTTGGCAA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000261584.9(PALB2):​c.1591_1600del​(p.Pro532AlafsTer26) 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 (★). Synonymous variant affecting the same amino acid position (i.e. L531L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 ENST00000261584.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.23

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 12 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 16-23634945-GAAGTTGGCAA-G is Pathogenic according to our data. Variant chr16-23634945-GAAGTTGGCAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 143965.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-23634945-GAAGTTGGCAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1591_1600del	p.Pro532AlafsTer26	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.1591_1600del	p.Pro532AlafsTer26	frameshift_variant	4/13	1	NM_024675.4	ENSP00000261584	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

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

SNPedia

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Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Dec 23, 2019

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Florentia Fostira, Marc Tischkowitz. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The c.1591_1600del10 pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of 10 nucleotides at nucleotide positions 1591 to 1600, causing a translational frameshift with a predicted alternate stop codon (p.P532Afs*26). This variant was reported in cohorts of Greek patients with early onset breast cancer and a family history of breast cancer (Fostira F et al. J Med Genet, 2020 Jan;57:53-61). (Antoniou AC et al. N Engl J Med, 2014 Aug;371:497-506). 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776414; hg19: chr16-23646266;