chr16-23636146-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The ENST00000261584.9(PALB2):c.400G>A(p.Asp134Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,612,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. D134E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

PALB2
ENST00000261584.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: 0.0800

Publications

11 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: 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004504204).

BP6

Variant 16-23636146-C-T is Benign according to our data. Variant chr16-23636146-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126749.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00149 (227/151994) while in subpopulation AFR AF = 0.0053 (220/41480). AF 95% confidence interval is 0.00473. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261584.9. 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.400G>A	p.Asp134Asn	missense	Exon 4 of 13	NP_078951.2
PALB2	NM_001407296.1		c.340G>A	p.Asp114Asn	missense	Exon 3 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.400G>A	p.Asp134Asn	missense	Exon 4 of 12	NP_001394226.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.400G>A	p.Asp134Asn	missense	Exon 4 of 13	ENSP00000261584.4
PALB2	ENST00000568219.5	TSL:1	c.-486G>A		5_prime_UTR	Exon 4 of 13	ENSP00000454703.2
PALB2	ENST00000561514.3	TSL:5	c.406G>A	p.Asp136Asn	missense	Exon 4 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

227

AN:

151876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00532

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000303

AC:

AN:

250744

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00437

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1460730

Hom.:

Cov.:

AF XY:

0.0000936

AC XY:

AN XY:

726560

show subpopulations

African (AFR)

AF:

0.00402

AC:

134

AN:

33354

American (AMR)

AF:

0.000225

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111536

Other (OTH)

AF:

0.000298

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00149

AC:

227

AN:

151994

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00530

AC:

220

AN:

41480

American (AMR)

AF:

0.000197

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00143

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000443

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.00546

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000436

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Familial cancer of breast (5)

Hereditary cancer-predisposing syndrome (3)

Breast and/or ovarian cancer (1)

Hereditary breast ovarian cancer syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.11

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

PhyloP100

0.080

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.30

REVEL

Benign

0.041

Sift

Benign

0.38

Sift4G

Benign

0.49

Polyphen

0.019

Vest4

0.12

MVP

0.24

MPC

0.089

ClinPred

0.00066

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.019

gMVP

0.048

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over