16-23603471-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_ModeratePS3PP5_Very_Strong

The NM_024675.4(PALB2):c.3549C>G(p.Tyr1183*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,612,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000253945: Experimental studies have shown that this premature translational stop signal affects PALB2 function (PMID:17200671, 19609323)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y1183Y) has been classified as Uncertain significance. The gene PALB2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

PALB2
NM_024675.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28O:2

Conservation

PhyloP100: 0.163

Publications

52 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
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 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_024675.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00337 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000253945: Experimental studies have shown that this premature translational stop signal affects PALB2 function (PMID: 17200671, 19609323).; SCV000183885: An individual with clinical features of Fanconi Anemia-N (FA-N) who carried p.Y1183* in conjunction with a PALB2 frameshift mutation was found to have no detectable PALB2 protein in lymphoblastoid cells (Reid S et al. Nat. Genet. 2007 Feb;39:162-4).; SCV000686050: A functional study has reported that this variant disrupted PALB2 function in a homology-mediated DNA repair and cisplatin-sensitivity assays (PMID: 31757951).; SCV000211538: Published functional studies demonstrate a damaging effect: defective homologous recombination (HR) efficiency, reduced resistance to cisplatin and PARP, and increased mitotic index indicating a defective checkpoint (Boonan 2019);; SCV000604598: cells derived from individuals with this variant do not produce PALB2 protein (Reid 2007).; SCV000821759: Experimental studies have shown that this variant prevents closure of the WD40 ring structure and destabilizes the PALB2 protein in cell culture (PMID: 19609323).; SCV001470046: Functional studies also show this variant causes defective DNA repair and lacks cisplatin resistance (PMID: 31757951 (2019)).; SCV001550311: Analysis of the PALB2 protein structure likely explains this protein absence as this variant is predicted to destabilize the PALB2 protein by preventing closure of the ring structure, resulting in incomplete protein folding and rapid degradation (Oliver 2009).; SCV001451483: Structural studies based on X-ray crystallography predict that loss of the last four residues of PALB2 caused by p.Tyr1183Ter disrupts the hydrogen bonding in the seventh blade of the beta-propeller, resulting in a misfolded and quickly degraded protein (Oliver et al. 2009).

PP5

Variant 16-23603471-G-C is Pathogenic according to our data. Variant chr16-23603471-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PALB2	NM_024675.4	MANE Select	c.3549C>G	p.Tyr1183*	stop_gained	Exon 13 of 13	NP_078951.2
PALB2	NM_001407296.1		c.3489C>G	p.Tyr1163*	stop_gained	Exon 12 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.3477C>G	p.Tyr1159*	stop_gained	Exon 12 of 12	NP_001394226.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3549C>G	p.Tyr1183*	stop_gained	Exon 13 of 13	ENSP00000261584.4	Q86YC2
PALB2	ENST00000568219.5	TSL:1	c.2664C>G	p.Tyr888*	stop_gained	Exon 13 of 13	ENSP00000454703.2	H3BN63
PALB2	ENST00000561514.3	TSL:5	c.3555C>G	p.Tyr1185*	stop_gained	Exon 13 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000159

AC:

AN:

251420

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1459918

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1110238

Other (OTH)

AF:

0.0000166

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cancer of breast (8)

not provided (6)

Hereditary cancer-predisposing syndrome (5)

Inherited breast cancer and ovarian cancer (3)

Fanconi anemia complementation group N (2)

Hereditary breast ovarian cancer syndrome (1)

PALB2-related cancer predisposition (1)

PALB2-related disorder (1)

Pancreatic cancer, susceptibility to, 3 (1)

Breast-ovarian cancer, familial, susceptibility to, 5 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.14

PhyloP100

0.16

Mutation Taster

=20/180

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over