rs876659859

Variant names:

• chr16-23607864-C-T
• rs876659859
• NM_024675.4:c.3350G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-23607864-C-T
• chr16-23607864-C-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PVS1 PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3350G>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 1117 (p.Arg1117Lys); however, RNA analysis demonstrated that the variant impacts splicing, leading to exon 12 skipping (r.3202_3350del149, p.Gly1068ValfsTer5) and a translational frameshift with 100% allele bias and no wild-type splice events harboring the variant (Ambry Genetics). The resulting mRNA is not predicted to undergo nonsense-mediated decay, but impacts the WD40 domain, which is a functionally important region. This variant is absent from gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been observed in combination with a PALB2 exon 11 duplication, which is classified as pathogenic, in at least four adult individuals without Fanconi Anemia (Ambry Genetics and Invitae). Although the phase of the variants was not confirmed, evidence from these individuals was not used to apply BS2 on the basis that multiple co-occurrences of this variant with the exon 11 duplication in unrelated individuals suggests these variants are more likely to be in cis. In summary, this variant meets the criteria to be classified as pathogenic 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(RNA), PM2_Supporting, PM5_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10579920/MONDO:0016419/020

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:4
• Conservation: PhyloP100: 5.18
• 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: 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 10 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

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.3350G>A	p.Arg1117Lys	missense splice_region	Exon 12 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.3290G>A	p.Arg1097Lys	missense splice_region	Exon 11 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.3278G>A	p.Arg1093Lys	missense splice_region	Exon 11 of 12	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3350G>A	p.Arg1117Lys	missense splice_region	Exon 12 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2465G>A	p.Arg822Lys	missense splice_region	Exon 12 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.3356G>A	p.Arg1119Lys	missense splice_region	Exon 12 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727076

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

American (AMR) AF: 0.00 AC: 0 AN: 44714

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111908

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Familial cancer of breast (2)
1	1	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 5 (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	not provided (1)
-	1	-	not specified (1)
1	-	-	PALB2-related cancer predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.25
Sift	Uncertain	0.023	D
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.45		Gain of methylation at R1117 (P = 0.0114)
MVP		0.76
MPC		0.16
ClinPred		0.86	D
GERP RS		6.1
Varity_R		0.41
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs876659859; hg19: chr16-23619185;