chr16-23636148-C-G

Variant names:

• chr16-23636148-C-G
• rs864622411
• ENST00000568219.5:c.-488G>C

Variant summary

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

The NM_001407304.1(PALB2):​c.-488G>C variant causes a 5 prime UTR premature start codon gain 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. 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_001407304.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -5.63
• Publications: 4 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 (MetaRNN=0.043474376).
• BP6: Variant 16-23636148-C-G is Benign according to our data. Variant chr16-23636148-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 837352.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407304.1. 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.398G>C	p.Ser133Thr	missense	Exon 4 of 13	NP_078951.2
	PALB2	NM_001407304.1		c.-488G>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 13	NP_001394233.1
	PALB2	NM_001407305.1		c.-488G>C		5_prime_UTR_premature_start_codon_gain	Exon 5 of 14	NP_001394234.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000568219.5	TSL:1	c.-488G>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 13	ENSP00000454703.2
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.398G>C	p.Ser133Thr	missense	Exon 4 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.-488G>C		5_prime_UTR	Exon 4 of 13	ENSP00000454703.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460778 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726618

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111496

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	Chordoma (1)
-	1	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.011
DANN	Benign	0.46
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-5.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.080
Sift	Benign	0.28	T
Sift4G	Benign	0.52	T
Polyphen		0.23	B
Vest4		0.12
MutPred		0.11		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.13
MPC		0.061
ClinPred		0.10	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.060
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs864622411; hg19: chr16-23647469;