16-23629828-A-AT

Position:

• chr16-23629828-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000261584.9(PALB2):​c.2325_2326insA​(p.Phe776IlefsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q775Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: PALB2 ENST00000261584.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -1.88

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-23629828-A-AT is Pathogenic according to our data. Variant chr16-23629828-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 232803.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.2325_2326insA	p.Phe776IlefsTer26	frameshift_variant	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2325_2326insA	p.Phe776IlefsTer26	frameshift_variant	5/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change creates a premature translational stop signal (p.Phe776Ilefs*26) 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: 24549055, 25575445). ClinVar contains an entry for this variant (Variation ID: 232803). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 22, 2021	- -
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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25575445, 24549055, 27631815, 24870022, 30772928, 30322717, 28779002, 32546565, 30303537, 33804961, 34113003) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 02, 2021	The c.2325dupA pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a duplication of A at nucleotide position 2325, causing a translational frameshift with a predicted alternate stop codon (p.F776Ifs*26). This alteration has been described in individuals with hereditary breast cancer and ovarian cancer (Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22(11):1305-13; Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149(2):547-54; Kotsopoulos J. Fam. Cancer 2017 01;16(1):29-34; Girard E et al. Int J Cancer. 2019 Apr 15;144(8):1962-1974). Of note, this mutation is also designated as c.2325_2326insA in published literature. 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	Dec 14, 2022	This variant inserts 1 nucleotide in exon 5 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. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24549055, 25575445, 27631815, 34113003). This variant also has been detected in a breast cancer case-control meta-analysis in 0/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010234). 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2023

The PALB2 c.2325dupA variant is predicted to result in a frameshift and premature protein termination (p.Phe776Ilefs*26). This variant has been reported in individuals with hereditary breast and ovarian cancer syndrome (Table 4, Castéra et al. 2014. PubMed ID: 24549055; Table 1, Kotsopoulos et al. 2017. PubMed ID: 27631815; Table 1, Nguyen-Dumont et al. 2015. PubMed ID: 25575445). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/232803/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs876659997; hg19: chr16-23641149;