16-23624027-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_024675.4(PALB2):c.2816T>G(p.Leu939Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00165 in 1,597,496 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L939F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:32

Conservation

PhyloP100: 5.59

Publications

60 publications found

Variant links:

COSMIC-nc: COSV104552826

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

PALB2 links:

PALB2-AS1 (HGNC:58305):

PALB2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1670264).

BP6

Variant 16-23624027-A-C is Benign according to our data. Variant chr16-23624027-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126683.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.2816T>G	p.Leu939Trp	missense	Exon 8 of 13	NP_078951.2
PALB2	NM_001407296.1		c.2756T>G	p.Leu919Trp	missense	Exon 7 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.2744T>G	p.Leu915Trp	missense	Exon 7 of 12	NP_001394226.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.2816T>G	p.Leu939Trp	missense	Exon 8 of 13	ENSP00000261584.4
PALB2	ENST00000568219.5	TSL:1	c.1931T>G	p.Leu644Trp	missense	Exon 8 of 13	ENSP00000454703.2
PALB2	ENST00000561514.3	TSL:5	c.2822T>G	p.Leu941Trp	missense	Exon 8 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000925

AC:

232

AN:

250918

AF XY:

0.000943

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00161

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00170

AC:

2460

AN:

1445198

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1180

AN XY:

719916

show subpopulations

African (AFR)

AF:

0.000212

AC:

AN:

33088

American (AMR)

AF:

0.000582

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85894

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00207

AC:

2270

AN:

1096942

Other (OTH)

AF:

0.00155

AC:

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

109

217

326

434

543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.00116

AC:

176

AN:

152298

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41562

American (AMR)

AF:

0.000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00198

AC:

135

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00183

Hom.:

Bravo

AF:

0.00115

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.000939

AC:

114

EpiCase

AF:

0.00213

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (13)

Familial cancer of breast (6)

Hereditary cancer-predisposing syndrome (6)

not specified (5)

Breast and/or ovarian cancer (1)

Fanconi anemia complementation group N (1)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

PALB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.060

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.6

PhyloP100

5.6

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.91

MVP

0.68

MPC

0.43

ClinPred

0.13

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.66

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

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