rs587776405

Positions:

• chr16-23641110-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_024675.4(PALB2):​c.48G>A​(p.Lys16=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.38

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-23641110-C-T is Pathogenic according to our data. Variant chr16-23641110-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23641110-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4	c.48G>A	p.Lys16=	splice_region_variant, synonymous_variant	1/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.48G>A	p.Lys16=	splice_region_variant, synonymous_variant	1/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 06, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 24556926]. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Sep 26, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 16 of the PALB2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant has been observed in individual(s) with breast cancer (PMID: 24556926). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of cryptic splice sites and introduces a premature termination codon (PMID: 24556926; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 143978). -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 27, 2019	This variant causes a G>A nucleotide substitution at the last position of exon 1 of the PALB2 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies have shown that this variant causes loss of the canonical donor site of intron 1, resulting in use of an upstream cryptic donor site and a transcript that lacks 17 nucleotides at the 3′ end of exon 1. At the protein level this is expected to result in a frameshift and loss of protein function (p.Cys11fs). This variant has been reported in an individual affected with hereditary breast cancer in the literature (PMID 24556926, 25099575). 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. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 2017	The c.48G>A variant (also known as p.K16K), located in coding exon 1 of the PALB2 gene, results from a G to A substitution at nucleotide position 48. This nucleotide substitution does not change the amino acid at codon 16. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. In one assay using lymphoblastoid cell lines from a patient with the c.48G>A alteration, the canonical donor splice site was abolished and an alternative splice site was used resulting in an aberrant transcript and a premature termination codon. The aberrant transcript was not present in one control, and reportedly absent in additional controls from individuals with mutations in other genes and from blood donors (Catucci I et al. Genet. Med. 2014 Sep;16:688-94). In addition, this alteration has been reported in patients with familial breast cancer (Catucci I et al. Genet. Med. 2014 Sep;16:688-94; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

SNPedia

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: -9
DS_DL_spliceai		0.94		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776405; hg19: chr16-23652431;