Variant rs45487491 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_024675.4(PALB2):c.768C>T(p.Ser256=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 1 hom. )

Consequence

PALB2
NM_024675.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 1.05

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 (BayesDel_noAF=-0.77).

BP6

Variant 16-23635778-G-A is Benign according to our data. Variant chr16-23635778-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 184338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.05 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.768C>T	p.Ser256=	synonymous_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.768C>T	p.Ser256=	synonymous_variant	4/13	1	NM_024675.4	ENSP00000261584	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251378

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000828

AC:

121

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 08, 2018	- -
Likely benign, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 30, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 16, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PALB2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 10, 2015	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 16, 2021	- -

PALB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 09, 2019

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). -

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

Mar 09, 2023

- -

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.Ser256= variant was identified in 1 of 5838 proband chromosomes (frequency: 0.00017) from individuals or families with hereditary breast cancer and was present in 1 of 2168 control chromosomes (frequency: 0.00046) from healthy individuals (Rahman_2007, Thompson_2015). The variant was also identified in dbSNP (ID: rs45487491) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (as likely benign by Ambry Genetics, Invitae, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Quest Diagnostics, Color Genomics, and Integrated Genetics), Clinvitae (as in ClinVar), and Cosmic (in endometrioid carcinoma). The variant was not identified in MutDB, LOVD 3.0, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 38 of 277166 chromosomes at a frequency of 0.000137 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 24030 chromosomes (freq: 0.000167), Other in 1 of 6464 chromosomes (freq: 0.000155), Latino in 1 of 34420 chromosomes (freq: 0.000029), European (Non-Finnish) in 7 of 126666 chromosomes (freq: 0.000055), East Asian in 13 of 18868 chromosomes (freq: 0.000689), and South Asian in 12 of 30780 chromosomes (freq: 0.00039); it was not observed in the Ashkenazi Jewish, or European (Finnish) populations. The p.Ser256= 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

-0.77

CADD

Benign

7.2

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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