16-23634870-T-C

Position:

chr16-23634870-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024675.4(PALB2):c.1676A>G(p.Gln559Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,613,096 control chromosomes in the GnomAD database, including 8,861 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1527 hom., cov: 32)

Exomes 𝑓: 0.095 ( 7334 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20O:1

Conservation

PhyloP100: 0.387

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005137205).

BP6

Variant 16-23634870-T-C is Benign according to our data. Variant chr16-23634870-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 126613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23634870-T-C is described in Lovd as [Benign]. Variant chr16-23634870-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 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.1676A>G	p.Gln559Arg	missense_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.1676A>G	p.Gln559Arg	missense_variant	4/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19497

AN:

151978

Hom.:

1516

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.0979

Gnomad ASJ

AF:

0.0907

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0928

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.0884

Gnomad OTH

AF:

0.127

GnomAD3 exomes

AF:

0.104

AC:

26075

AN:

249632

Hom.:

1534

AF XY:

0.103

AC XY:

13959

AN XY:

134980

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.0773

Gnomad ASJ exome

AF:

0.0763

Gnomad EAS exome

AF:

0.174

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0960

Gnomad NFE exome

AF:

0.0883

Gnomad OTH exome

AF:

0.100

GnomAD4 exome

AF:

0.0950

AC:

138857

AN:

1461000

Hom.:

7334

Cov.:

AF XY:

0.0953

AC XY:

69269

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.218

Gnomad4 AMR exome

AF:

0.0822

Gnomad4 ASJ exome

AF:

0.0769

Gnomad4 EAS exome

AF:

0.192

Gnomad4 SAS exome

AF:

0.104

Gnomad4 FIN exome

AF:

0.0931

Gnomad4 NFE exome

AF:

0.0873

Gnomad4 OTH exome

AF:

0.109

GnomAD4 genome

AF:

0.129

AC:

19545

AN:

152096

Hom.:

1527

Cov.:

AF XY:

0.128

AC XY:

9543

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.214

Gnomad4 AMR

AF:

0.0977

Gnomad4 ASJ

AF:

0.0907

Gnomad4 EAS

AF:

0.173

Gnomad4 SAS

AF:

0.103

Gnomad4 FIN

AF:

0.0928

Gnomad4 NFE

AF:

0.0884

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.0996

Hom.:

1458

Bravo

AF:

0.134

TwinsUK

AF:

0.0879

AC:

326

ALSPAC

AF:

0.0830

AC:

320

ESP6500AA

AF:

0.221

AC:

970

ESP6500EA

AF:

0.0909

AC:

782

ExAC

AF:

0.106

AC:

12905

Asia WGS

AF:

0.149

AC:

516

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided

Benign:4

Benign, no assertion criteria provided	curation	Leiden Open Variation Database	Aug 07, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Yukihide Momozawa. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 33169439, 31636395, 31757951, 30521987, 28492530, 29052111, 24728327, 26283626, 27648926, 27153395, 24206657) -

Familial cancer of breast

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Fanconi anemia complementation group N

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Breast-ovarian cancer, familial, susceptibility to, 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

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

0.064

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.40

DANN

Benign

0.094

DEOGEN2

Benign

0.015

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.20

T;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.41

.;N

PrimateAI

Benign

0.19

PROVEAN

Benign

0.63

N;N

REVEL

Benign

0.023

Sift

Benign

1.0

T;T

Sift4G

Benign

0.87

T;T

Polyphen

0.0

.;B

Vest4

0.037

MPC

0.055

ClinPred

0.00026

GERP RS

-2.7

Varity_R

0.022

gMVP

0.11

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