rs57605939

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_024675.4(PALB2):c.629C>T(p.Pro210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,614,072 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. P210T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 93 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 98 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:22O:1

Conservation

PhyloP100: 0.357

Publications

19 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: 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

PALB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025817156).

BP6

Variant 16-23635917-G-A is Benign according to our data. Variant chr16-23635917-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126761.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.066 is higher than 0.05.

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.629C>T	p.Pro210Leu	missense	Exon 4 of 13	NP_078951.2
PALB2	NM_001407296.1		c.569C>T	p.Pro190Leu	missense	Exon 3 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.629C>T	p.Pro210Leu	missense	Exon 4 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.629C>T	p.Pro210Leu	missense	Exon 4 of 13	ENSP00000261584.4	Q86YC2
PALB2	ENST00000568219.5	TSL:1	c.-257C>T		5_prime_UTR	Exon 4 of 13	ENSP00000454703.2	H3BN63
PALB2	ENST00000561514.3	TSL:5	c.635C>T	p.Pro212Leu	missense	Exon 4 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2942

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00477

AC:

1199

AN:

251404

AF XY:

0.00364

show subpopulations

Gnomad AFR exome

AF:

0.0655

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00197

AC:

2879

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1229

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0703

AC:

2354

AN:

33478

American (AMR)

AF:

0.00382

AC:

171

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000104

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1111998

Other (OTH)

AF:

0.00454

AC:

274

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

187

374

562

749

936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0195

AC:

2969

AN:

152208

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1427

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0681

AC:

2827

AN:

41522

American (AMR)

AF:

0.00707

AC:

108

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68020

Other (OTH)

AF:

0.0128

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

144

288

432

576

720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00800

Hom.:

Bravo

AF:

0.0223

ESP6500AA

AF:

0.0649

AC:

285

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00618

AC:

750

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Familial cancer of breast (5)

Hereditary cancer-predisposing syndrome (5)

not provided (2)

Breast and/or ovarian cancer (1)

Fanconi anemia complementation group N (1)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

PhyloP100

0.36

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.096

Sift

Benign

0.13

Sift4G

Benign

0.79

Polyphen

0.021

Vest4

0.11

MVP

0.31

MPC

0.059

ClinPred

0.0056

GERP RS

0.37

Varity_R

0.033

gMVP

0.16

Mutation Taster

=97/3

polymorphism (auto)

(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

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