rs515726129

Variant names:

• chr16-23638095-T-C
• rs515726129
• ENST00000568219.5:c.-803A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-23638095-T-C
• chr16-23638095-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001407304.1(PALB2):​c.-803A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PALB2 NM_001407304.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.85
• Publications: 11 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3998338).

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.83A>G	p.Tyr28Cys	missense	Exon 2 of 13	NP_078951.2
	PALB2	NM_001407304.1		c.-803A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001394233.1	H3BN63
	PALB2	NM_001407305.1		c.-803A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	NP_001394234.1	H3BN63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000568219.5	TSL:1	c.-803A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.83A>G	p.Tyr28Cys	missense	Exon 2 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-803A>G		5_prime_UTR	Exon 2 of 13	ENSP00000454703.2	H3BN63

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727198

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

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: 8.99e-7 AC: 1 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Familial cancer of breast (3)
-	2	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.20		Gain of methylation at K25 (P = 0.0941)
MVP		0.85
MPC		0.38
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.53
gMVP		0.22
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		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: rs515726129; hg19: chr16-23649416;