rs515726123

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_024675.4(PALB2):c.509_510delGA(p.Arg170IlefsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001366810: PS3, PS4_STR *Note: Since the input directly mentions PS3, it is treated as providing evidence for PS3 without needing to extract a specific snippet.* However, based on the instructions and examples provided, the correct response should be: **Output**: `no`" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R170R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene PALB2 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

PALB2
NM_024675.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:51O:1

Conservation

PhyloP100: -0.0180

Publications

36 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 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001366810: PS3, PS4_STR *Note: Since the input directly mentions PS3, it is treated as providing evidence for PS3 without needing to extract a specific snippet.* However, based on the instructions and examples provided, the correct response should be: **Output**: `no`; SCV000185544: Further, a functional characterization of this alteration showed that the truncated protein results in weakly bound DNA substrates, suggesting that the loss of the second DNA binding domain affects the affinity for DNA, resulting in significantly impaired DNA binding (Pauty J et al. Nucleic Acids Res. 2017 Mar;45:2644-2657).; SCV000686065: A functional study reported that this variant impacts PALB2 binding to DNA (PMID: 28158555).; SCV000601792: Functional studies in the published literature report this variant reduced DNA binding and failed to stimulate RAD51-mediated strand invasion (PMID: 28158555 (2017)).; SCV001623425: Experimental evidence evaluating an impact on protein function demonstrated the variant impairs DNA binding ability, fails to stimulate RAD51 and fails to localize to DNA damage sites (Pauty_2017).

PP5

Variant 16-23636035-ATC-A is Pathogenic according to our data. Variant chr16-23636035-ATC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 126757.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.509_510delGA	p.Arg170IlefsTer14	frameshift	Exon 4 of 13	NP_078951.2
PALB2	NM_001407296.1		c.449_450delGA	p.Arg150IlefsTer14	frameshift	Exon 3 of 12	NP_001394225.1
PALB2	NM_001407297.1		c.509_510delGA	p.Arg170IlefsTer14	frameshift	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.509_510delGA	p.Arg170IlefsTer14	frameshift	Exon 4 of 13	ENSP00000261584.4	Q86YC2
PALB2	ENST00000568219.5	TSL:1	c.-377_-376delGA		5_prime_UTR	Exon 4 of 13	ENSP00000454703.2	H3BN63
PALB2	ENST00000561514.3	TSL:5	c.515_516delGA	p.Arg172IlefsTer14	frameshift	Exon 4 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251446

AF XY:

0.0000294

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:

0.0000703

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461880

Hom.:

AF XY:

0.0000179

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.0000113

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (17)

Familial cancer of breast (11)

Hereditary cancer-predisposing syndrome (8)

Breast and/or ovarian cancer (2)

Breast-ovarian cancer, familial, susceptibility to, 5 (2)

Malignant tumor of breast (2)

PALB2-related disorder (2)

Breast carcinoma (1)

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

Carcinoma of pancreas (1)

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

Hereditary breast ovarian cancer syndrome (1)

not specified (1)

Pancreatic cancer, susceptibility to, 3;C3469522:Breast cancer, susceptibility to (1)

Hereditary cancer-predisposing syndrome;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.018

Mutation Taster

=0/200

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