Variant rs587782050 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024675.4(PALB2):c.3476G>T(p.Trp1159Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 4.92

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 links:

PALB2 (HGNC:):

PALB2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3476G>T	p.Trp1159Leu	missense_variant	13/13	ENST00000261584.9	NP_078951.2	Q86YC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.3476G>T	p.Trp1159Leu	missense_variant	13/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151910

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74180

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 20, 2019	This missense variant replaces tryptophan with leucine at codon 1159 of the PALB2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2023	The p.W1159L variant (also known as c.3476G>T), located in coding exon 13 of the PALB2 gene, results from a G to T substitution at nucleotide position 3476. The tryptophan at codon 1159 is replaced by leucine, an amino acid with similar properties. In a homology-directed DNA repair (HDR) and PARP inhibitor sensitivity assays, this alteration was found to be functionally normal (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 460996). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 1159 of the PALB2 protein (p.Trp1159Leu). -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 16, 2024	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2023

Variant summary: PALB2 c.3476G>T (p.Trp1159Leu) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3476G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homologous recombination or in a PARP inhibitor sensitivity assay (e.g., Boonen_2019). The following publication was ascertained in the context of this evaluation (PMID: 31757951). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate: protein production, homologous recombination efficiency, and sensitivity to PARP inhibition to proliferation similar to wildtype (Boonen et al., 2019); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 28152038, 31757951) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-9.7

D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0060

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.75

MutPred

0.60

.;Loss of catalytic residue at W1159 (P = 0.0064);

MVP

0.67

MPC

0.44

ClinPred

1.0

GERP RS

5.8

Varity_R

0.92

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over