rs57605939

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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 0.020 ( 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:21O:1

Conservation

PhyloP100: 0.357

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 Benign. Variant got -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 id is 126761.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=12, not_provided=1, Uncertain_significance=1}. Variant chr16-23635917-G-A is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.629C>T	p.Pro210Leu	missense_variant	4/13	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.629C>T	p.Pro210Leu	missense_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

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

GnomAD3 exomes

AF:

0.00477

AC:

1199

AN:

251404

Hom.:

AF XY:

0.00364

AC XY:

494

AN XY:

135886

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.0703

Gnomad4 AMR exome

AF:

0.00382

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.00454

GnomAD4 genome

AF:

0.0195

AC:

2969

AN:

152208

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1427

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0681

Gnomad4 AMR

AF:

0.00707

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00385

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:21Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 26, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as 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. -

Familial cancer of breast

Uncertain:1Benign:3

Benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327) -

Fanconi anemia complementation group N

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 11, 2019

- -

Malignant tumor of breast

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Pro210Leu variant was identified in 65 of 10554 proband chromosomes (frequency: 0.006) from individuals or families with breast cancer and was present in 37 of 8955 control chromosomes (frequency: 0.0005) from healthy individuals (Rahman_2007_17200668, Garcia_2009_18302019, Ding_2011_21113654, Zheng_2012_21932393, Tischkowitz_2012_22241545, Thompson_2015_26283626). The variant was also identified in the following databases: dbSNP (ID: rs57605939) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (8x, as benign by Invitae, Ambry, EGL Genetic, Color Genomics, Illumina, Pathway Genomics, PALB2 database, 2x as likely benign, by Cancer Genetics, Institute for Biomarker, 1x as uncertain significant by ITMI), Clinvitae (3x as benign and 3x with conflicting interpretations of pathogenicity by ClinVar and EmvClass), LOVD 3.0 (5x). The variant was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1750 of 277182 chromosomes (51 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1618 of 24022 chromosomes (freq: 0.07), other in 13 of 6468 chromosomes (freq: 0.002), Latino in 105 of 34420 chromosomes (freq: 0.003), European Non-Finnish in 10 of 126682 chromosomes (freq: 0.00008), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian, European Finnish, populations. The p.Pro210Leu 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.1

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

MutationTaster

Benign

1.0

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

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