rs878855106

Variant names:

• chr16-23636337-G-A
• rs878855106
• NM_024675.4:c.212-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23636337-G-A
• chr16-23636337-G-C
• chr16-23636337-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_024675.4(PALB2):​c.212-3C>T variant causes a splice region, intron 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALB2 NM_024675.4 splice_region, intron
• Scores: Splicing: ADA: 0.001759
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.532
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 16-23636337-G-A is Benign according to our data. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540. Variant chr16-23636337-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241540.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.212-3C>T		splice_region_variant, intron_variant	Intron 3 of 12	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.212-3C>T		splice_region_variant, intron_variant	Intron 3 of 12	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1431282 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 711206

African (AFR) AF: 0.00 AC: 0 AN: 32432

American (AMR) AF: 0.00 AC: 0 AN: 41566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25634

East Asian (EAS) AF: 0.00 AC: 0 AN: 38754

South Asian (SAS) AF: 0.00 AC: 0 AN: 81540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094574

Other (OTH) AF: 0.00 AC: 0 AN: 59064

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:1 Benign:1

Jan 10, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 241540). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 4 in the PALB2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.1
DANN	Benign	0.39
PhyloP100		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs878855106; hg19: chr16-23647658;