rs786203245

Variant names:

• chr16-23638131-T-A
• rs786203245
• NM_024675.4:c.49-2A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23638131-T-A
• chr16-23638131-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.49-2A>T variant in PALB2 occurs within the canonical splice acceptor site (-1,2) of intron 1. The computational splicing predictor SpliceAI gives a score of 0.97 for acceptor loss and 0.71 score for an acceptor gain, predicting that the variant disrupts the acceptor splice site. This alteration is predicted to result in an in-frame loss impacting two amino acids from of exon 2 in the coiled-coiled domain with unknown functional impact (PMID:30890586, 30289697, 31159747, Ambry Genetics). This variant is absent in gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1_Moderate, PM2_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA195965/MONDO:0016419/020

• 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: Uncertain significance reviewed by expert panel P:3 U:4
• Conservation: PhyloP100: 3.19
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.49-2A>T		splice_acceptor_variant, intron_variant	Intron 1 of 12	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.49-2A>T		splice_acceptor_variant, intron_variant	Intron 1 of 12	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461168 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111346

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial cancer of breast Pathogenic:2 Uncertain:3

Apr 05, 2023

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.49-2A>T variant in PALB2 occurs within the canonical splice acceptor site (-1,2) of intron 1. The computational splicing predictor SpliceAI gives a score of 0.97 for acceptor loss and 0.71 score for an acceptor gain, predicting that the variant disrupts the acceptor splice site. This alteration is predicted to result in an in-frame loss impacting two amino acids from of exon 2 in the coiled-coiled domain with unknown functional impact (PMID: 30890586, 30289697, 31159747, Ambry Genetics). This variant is absent in gnomAD v2.1.1. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1_Moderate, PM2_Supporting) -

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 1 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with PALB2-related conditions (PMID: 25452441, 29478780). ClinVar contains an entry for this variant (Variation ID: 186820). Studies have shown disruption of this splice site is associated with skipping of 2 amino acids, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 30890586, 34846068). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 27, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2019

Leiden Open Variation Database

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -

Feb 06, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 03, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 2 in the PALB2 gene. This alteration was identified in 1/1824 triple-negative breast cancer patients unselected for family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb; 33(4):304-11). 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 and will result in the creation or strengthening of a novel splice acceptor site. Usage of this novel acceptor site would result in an in-frame transcript lacking two highly conserved amino acids in the coiled-coiled domain and is predicted to significantly disrupt a protein-protein interface (Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Valenzuela-Palomo A et al. J Pathol, 2022 Mar;256:321-334). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Dec 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25452441, 29478780, 30128536, 34846068, 30890586) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		3.2
GERP RS		5.5
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.71		Position offset: -8
DS_AL_spliceai		0.97		Position offset: -2

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

Other links and lift over

dbSNP: rs786203245; hg19: chr16-23649452;