rs373478248

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_024675.4(PALB2):c.2289G>C(p.Leu763Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:9

Conservation

PhyloP100: 1.06

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035972476).

BP6

Variant 16-23629865-C-G is Benign according to our data. Variant chr16-23629865-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136133.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=6}. Variant chr16-23629865-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.2289G>C	p.Leu763Phe	missense_variant	5/13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.2289G>C	p.Leu763Phe	missense_variant	5/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

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

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251480

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000962

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 28, 2023	In the published literature, the variant has been reported in individuals with breast cancer as well as in healthy controls (PMID: 32068069 (2020), 30287823 (2018), 28825143 (2017), 26283626 (2015), 25186627 (2015), 23977390 (2013), 33471991 (2021) and LOVD (http://databases.lovd.nl/shared/genes/PALB2)). In addition, a functional study suggests that this variant is not damaging to the homology-directed DNA repair activity of PALB2, however, further studies are necessary to confirm this finding (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.0007 (14/19950 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2021	This variant is associated with the following publications: (PMID: 28678401, 26283626, 23977390, 26689913, 28825143, 28779002, 25186627, 25225064, 30287823, 29338689, 30093976, 30447919, 31636395) -

not specified

Uncertain:2Benign:3

Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 05, 2020	Variant summary: PALB2 c.2289G>C (p.Leu763Phe) results in a non-conservative amino acid change located in the MRG15 interaction domain (Zhang_PALB2_BCRT_2017) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251480 control chromosomes, predominantly at a frequency of 0.00065 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2289G>C has been reported in the literature in individuals affected with Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Wiltshire_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=3, VUS n=7). Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2019	The PALB2 c.2289G>C; p.Leu763Phe variant (rs373478248) is reported in Eastern Asian individuals with familial or sporadic breast cancer as well as healthy controls (Momozawa 2018, Zhang 2017). This variant is reported as likely benign or uncertain in ClinVar (Variation ID: 136133). It is found in the general East Asian population with an allele frequency of 0.07% (14/19950 alleles) in the Genome Aggregation Database. The leucine at codon 763 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. REFERENCES Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083 Zhang K et al. Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer. Breast Cancer Res Treat. 2017 Dec;166(3):865-873. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial cancer of breast

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 04, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 25, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 13, 2017	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 18, 2020

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Leu763Phe variant was identified in 3 of 4236 proband chromosomes (frequency: 0.0007) from Asian and Australian individuals or families with breast and ovarian cancer (Phuah 2013, Thompson 2015). The variant was also identified in dbSNP (ID: rs373478248) as With other allele, ClinVar (1x likely benign: Invitae; 4x uncertain significance: Ambry Genetics, GeneDx, Peter MacCullum Cancer Centre, Color Genomics), LOVD 3.0 (2x likely does not affect function), databases. The variant was not identified in COSMIC, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 14 of 277240 chromosomes at a frequency of 0.00005 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Leu763Phe residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

PALB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T

Eigen

Benign

-0.041

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.074

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

1.0

.;D

Vest4

0.27

MutPred

0.20

.;Gain of methylation at K764 (P = 0.0322);

MVP

0.39

MPC

0.31

ClinPred

0.12

GERP RS

4.0

Varity_R

0.075

gMVP

0.086

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