Genetic Variant NM_024675.4:c.2590C>T (chr16-23626394-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024675.4(PALB2):c.2590C>T(p.Pro864Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,614,176 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P864L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 11 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:34O:1

Conservation

PhyloP100: 0.823

Publications

43 publications found

Variant links:

COSMIC-nc: COSV99848803

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00803414).

BP6

Variant 16-23626394-G-A is Benign according to our data. Variant chr16-23626394-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00279 (425/152300) while in subpopulation AMR AF = 0.00451 (69/15300). AF 95% confidence interval is 0.00366. There are 0 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 11 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.2590C>T	p.Pro864Ser	missense	Exon 7 of 13	NP_078951.2
PALB2	NM_001407296.1		c.2530C>T	p.Pro844Ser	missense	Exon 6 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.2518C>T	p.Pro840Ser	missense	Exon 6 of 12	NP_001394226.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PALB2	ENST00000261584.9	TSL:1 MANE Select	c.2590C>T	p.Pro864Ser	missense	Exon 7 of 13	ENSP00000261584.4
PALB2	ENST00000568219.5	TSL:1	c.1705C>T	p.Pro569Ser	missense	Exon 7 of 13	ENSP00000454703.2
PALB2	ENST00000561514.3	TSL:5	c.2596C>T	p.Pro866Ser	missense	Exon 7 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

427

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00376

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00284

AC:

715

AN:

251474

AF XY:

0.00292

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00392

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00348

AC:

5084

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

2562

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33480

American (AMR)

AF:

0.00340

AC:

152

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

318

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000429

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00387

AC:

4308

AN:

1112006

Other (OTH)

AF:

0.00371

AC:

224

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

276

551

827

1102

1378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00279

AC:

425

AN:

152300

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41562

American (AMR)

AF:

0.00451

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00376

AC:

256

AN:

68030

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

119

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:

0.00410

Hom.:

Bravo

AF:

0.00304

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00266

AC:

323

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00533

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (14)

Hereditary cancer-predisposing syndrome (6)

Familial cancer of breast (5)

not specified (4)

Malignant tumor of breast (2)

Breast and/or ovarian cancer (1)

Breast carcinoma (1)

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

Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)

Fanconi anemia complementation group N (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0087

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.071

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.75

M_CAP

Benign

0.0078

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

0.82

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.062

Sift

Benign

0.12

Sift4G

Benign

0.72

Polyphen

0.58

Vest4

0.31

MVP

0.55

MPC

0.12

ClinPred

0.029

GERP RS

2.8

Varity_R

0.25

gMVP

0.35

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

SpliceAI score (max)

0.010

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