16-23635121-TG-T

Variant names:

• chr16-23635121-TG-T
• rs1555461295
• NM_024675.4:c.1424delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_024675.4(PALB2):​c.1424delC​(p.Ser475fs) 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. S475S) has been classified as Likely benign. 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:2
• Conservation: PhyloP100: 3.26

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23635121-TG-T is Pathogenic according to our data. Variant chr16-23635121-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 460893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635121-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.1424delC	p.Ser475fs	frameshift_variant	Exon 4 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.1424delC	p.Ser475fs	frameshift_variant	Exon 4 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:1

Feb 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in PALB2 are known to be pathogenic (PMID: 25099575, 17200668). This sequence change deletes 1 nucleotide from exon 4 of the PALB2 mRNA (c.1424delC), causing a frameshift at codon 475. This creates a premature translational stop signal (p.Ser475*) and is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1424delC pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 1424, causing a translational frameshift with a predicted alternate stop codon (p.S475*). 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

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs1555461295; hg19: chr16-23646442;