16-23624008-C-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_024675.4(PALB2):c.2834+1G>C variant causes a splice donor change. The variant allele was found at a frequency of 0.000000704 in 1,420,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.71

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• 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 16-23624008-C-G is Pathogenic according to our data. Variant chr16-23624008-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 482048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4	c.2834+1G>C		splice_donor_variant		ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9	c.2834+1G>C		splice_donor_variant		1	NM_024675.4	P1
	ENST00000561764.1	n.528C>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420920 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 709130

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2023

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with breast cancer (Rodriguez Balada et al., 2020); This variant is associated with the following publications: (PMID: 31786208) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2019

The c.2834+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 8 of the PALB2 gene. Though this exact alteration has not been reported in the literature, two other alterations at this same position (c.2834+1G>A and c.2834+1G>T) have been reported in probands with breast cancer (Susswein LR et al. Genet. Med., 2016 08;18:823-32; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 11, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 31786208, Invitae). Variant(s) at this splice site have also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 482048). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the PALB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776419; hg19: chr16-23635329;