rs587782566

Variant names:

• chr16-23607859-C-T
• rs587782566
• NM_024675.4:c.3350+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-23607859-C-T
• chr16-23607859-C-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The NM_024675.4(PALB2):​c.3350+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000186838: RNA analysis showed skipping of coding exon 12 (Mori M et al. Haematologica. 2019 Oct" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PALB2 NM_024675.4 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 3.40
• Publications: 9 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: Ambry Genetics
• PALB2-related cancer predisposition

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

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PALB2-AS1 (HGNC:58305):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186838: RNA analysis showed skipping of coding exon 12 (Mori M et al. Haematologica. 2019 Oct;104:1962-1973). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV001358405: Four RNA studies have reported aberrant mRNA transcripts in variant carriers and in one minigene splicing assay that are predicted to disrupt the BRCA2 and RAD51 binding domain in the protein (PMID: 30792206, 30890586, 32133419, 32238468, 34846068).; SCV000633424: Studies have shown that this variant results in the generation of two aberrant transcripts, one that leads to out-of-frame exon 12 skipping and the other that leads to the in-frame skipping of exons 11 and 12 together and introduces a new termination codon (PMID: 30890586, 32133419; internal data).; SCV004043220: mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 30792206, 32133419, 34846068].; SCV002074502: Experimental evidence from multiple studies demonstrate that this variant affects mRNA splicing leading to aberrant transcripts, most significantly to skipping of exon 12 (Karam_2019, Lopez-Perolio_2019, Mori_2019, Landrith_2020). The predicted protein encoded by this transcript is unlikely to be functional, as it lacks part of the C-terminal WD40 beta-propeller domain that mediates PALB2 interaction with several key homologous recombination proteins, including BRCA2 and RAD51 (Lopez-Perolio_2019, Landrith_2020).; SCV005347930: RNA studies indicate this variant causes exon 12 skipping (Mori et al. 2019. PubMed ID: 30792206; Lopez-Perolio et al. 2019. PubMed ID: 30890586; Valenzuela-Palomo et al. 2021. PubMed ID: 34846068).; SCV005623228: Assessment of experimental evidence suggests this variant results in abnormal RNA splicing, causing skipping of exon 12 (PMID: 30792206 (2019), 34846068 (2022)) or skipping of exons 11 and 12 (PMID: 30890586 (2019)).; SCV005909261: Functional analysis using RT-PCR and RNA sequencing revealed that this variant causes abnormal splicing, resulting in two distinct transcripts: one with exon 12 skipping and another with exon 11 and 12 skipping. The exon 11 and 12 skipping transcript causes an in-frame deletion of 78 amino acids (N1039-G1116) within the WD40 repeats domain of PALB2, which is critical for binding with RAD51C, RAD51, and BRCA2 in homologous recombination repair (Kang et al., 2024; PMID: 39999518).
• PP5: Variant 16-23607859-C-T is Pathogenic according to our data. Variant chr16-23607859-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.3350+5G>A		splice_region intron	N/A	NP_078951.2
	PALB2	NM_001407296.1		c.3290+5G>A		splice_region intron	N/A	NP_001394225.1
	PALB2	NM_001407297.1		c.3278+5G>A		splice_region intron	N/A	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3350+5G>A		splice_region intron	N/A	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2465+5G>A		splice_region intron	N/A	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.3356+5G>A		splice_region intron	N/A	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251408 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00000821 AC: 12 AN: 1461520 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727058

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.0000166 AC: 1 AN: 60360

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152288 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary cancer-predisposing syndrome (4)
3	-	-	Familial cancer of breast (3)
2	-	-	Breast-ovarian cancer, familial, susceptibility to, 5 (2)
2	-	-	not provided (2)
1	-	-	Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	PALB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.93
PhyloP100		3.4
Mutation Taster		=38/62	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.14		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: rs587782566; hg19: chr16-23619180;