Variant rs151162255 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_024675.4(PALB2):c.1606C>T(p.Leu536Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,614,152 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

PALB2
NM_024675.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.121

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-23634940-G-A is Benign according to our data. Variant chr16-23634940-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 126610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23634940-G-A is described in Lovd as [Likely_benign]. Variant chr16-23634940-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.121 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.1606C>T	p.Leu536Leu	synonymous_variant	4/13	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.1606C>T	p.Leu536Leu	synonymous_variant	4/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

267

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00635

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000478

GnomAD3 exomes

AF:

0.000441

AC:

111

AN:

251480

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00615

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00520

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.00175

AC:

267

AN:

152272

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00633

Gnomad4 AMR

AF:

0.000196

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:

0.000473

Alfa

AF:

0.000867

Hom.:

Bravo

AF:

0.00183

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2017	Variant summary: The PALB2 c.1606C>T (p.Leu536Leu) variant involves the alteration of a non-conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may eliminate ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 71/121918 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.006439 (67/10406). This frequency is about 41 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple publications have cited the variant in affected African-American individuals, although with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 2014	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. -

Familial cancer of breast

Benign:2

Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 31, 2021

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 28, 2022

- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Leu536= variant was identified in 6 of 558 proband chromosomes (frequency: 0.01075) from individuals or families with breast cancer and was present in 1 of 520 control chromosomes (frequency: 0.0019) from healthy individuals (Zheng 2012,). The variant was also identified in dbSNP (ID: rs151162255) as With other allele, ClinVar (classified as benign by GeneDX, Invitae; classified as likely benign by Ambry genetics, PALB2 database), Clinvitae (classified as benign by ClinVar), Zhejiang Colon Cancer Database (2X probably does not affect function), databases. The variant was identified in control databases in 160 of 277242 chromosomes at a frequency of 0.000577 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu536= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.50

DANN

Benign

0.42

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

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

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