16-23629276-C-G

Variant names:

• chr16-23629276-C-G
• rs587776417
• NM_024675.4:c.2515-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_024675.4(PALB2):​c.2515-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,460,682 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: 6.8e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.96
• Publications: 2 publications found

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]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02021904 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of 32, new splice context is: gagcttcctgcttctgatAGcat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-23629276-C-G is Pathogenic according to our data. Variant chr16-23629276-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 216006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.2515-1G>C		splice_acceptor intron	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.2455-1G>C		splice_acceptor intron	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.2514+364G>C		intron	N/A	NP_001394226.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.2515-1G>C		splice_acceptor intron	N/A	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.1630-1G>C		splice_acceptor intron	N/A	ENSP00000454703.2
	PALB2	ENST00000697380.1		n.1806G>C		non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251010 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460682 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726704

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111572

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 21, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); Has not been previously published as pathogenic or benign to our knowledge

Apr 01, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Variant identified at frequency that is consistent with pathogenicity.

Hereditary cancer-predisposing syndrome Pathogenic:2

May 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to C nucleotide substitution at the -1 position of intron 15 of the PALB2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A similar acceptor site variant at this intron, c.2515-1G>T, has been reported to cause the in-frame skipping of exon 16 (c.2515_2586del and p.Thr839_Lys862del) (PMID: 21285249) and also has been reported in two individuals affected with breast cancer and an individual affected with breast and pancreatic cancer (PMID: 19264984, 21285249). The in-frame skipping of exon 16 disrupts the WD40 repeat domain and it has been reported to produce a hypomorphic unstable PALB2 variant protein and is considered to be loss-of-function (PMID: 26990772, 30890586). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251010 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site, c.2515-1G>T and c.2515-1G>A, are known to be disease-causing (ClinVar variation ID: 126657, 582926). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

Dec 01, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2515-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 6 of the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1

Mar 13, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.96 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000216006). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Familial cancer of breast Pathogenic:1

Sep 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs587776417, gnomAD 0.003%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in skipping of 6, but is expected to preserve the integrity of the reading-frame (PMID: 21285249, 26990772, 30890586). ClinVar contains an entry for this variant (Variation ID: 216006). Disruption of this splice site has been observed in individual(s) with breast and pancreatic cancer (PMID: 19264984, 21285249). This sequence change affects an acceptor splice site in intron 5 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		4.0
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.96		Position offset: -1

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

Other links and lift over

dbSNP: rs587776417; hg19: chr16-23640597; COSMIC: COSV106407618;