chr16-23638125-T-C

Position:

chr16-23638125-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_024675.4(PALB2):c.53A>G(p.Lys18Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000921 in 1,613,708 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K18E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0049 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 4 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:23O:1

Conservation

PhyloP100: 4.85

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_024675.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008260548).

BP6

Variant 16-23638125-T-C is Benign according to our data. Variant chr16-23638125-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126758.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, not_provided=1, Likely_benign=4, Uncertain_significance=1}. Variant chr16-23638125-T-C is described in Lovd as [Likely_benign]. Variant chr16-23638125-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00487 (741/152252) while in subpopulation AFR AF= 0.0165 (686/41542). AF 95% confidence interval is 0.0155. There are 3 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.53A>G	p.Lys18Arg	missense_variant	2/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.53A>G	p.Lys18Arg	missense_variant	2/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00486

AC:

740

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0165

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00142

AC:

356

AN:

251468

Hom.:

AF XY:

0.00102

AC XY:

138

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.000925

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:

0.0000791

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000510

AC:

745

AN:

1461456

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

316

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.0153

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000756

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00487

AC:

741

AN:

152252

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

360

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0165

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000814

Hom.:

Bravo

AF:

0.00546

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0155

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00176

AC:

214

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:23Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:9Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 14, 2019	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 04, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 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	-	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PALB2 p.Lys18Arg variant was identified in 20 of 8974 proband chromosomes (frequency: 0.002) from German, Russian, French, (African) American and Australian individuals or families with breast cancer (BRCA1/2 negative or familial or early onset) and early onset prostate cancer, and was identified in 2 of 6682 chromosomes from healthy individuals (frequency: 0.0003) (Bogdanova_2011_21165770, Damiola_2015_26564480, Ding_2011_21113654 , Nguyen_Dumont_2015, Thompson_2015_26283626, Zheng_2012_21932393, Tischkowitz_2008_18288683, Bodian_2014_24728327). The variant was found in 1 proband with prostate cancer as well as his unaffected brother (Tischkowitz_2008_18288683). Functional analysis of PALB2 interaction with BRCA1 showed the variant did not significantly affect complex formation, while partially impairing HR (homologous recombination) DNA repair activity of PALB2 (Foo_2017_ 28319063). The variant was also identified in dbSNP (ID: rs138789658) â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (classified with conflicting interpretations of pathogencity; submitters: benign by GeneDx, Ambry Genetics, Invitae, Color Genomics, Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics) and Pathway Genomics; likely benign by PALB2 database, Genetic Services Laboratory (University of Chicago), Illumina; uncertain significance by Cancer Genetics Laboratoy (Peter MacCallum Cancer Center), and classification not provided by ITMI), Clinvitae (5x), LOVD 3.0 (1x), Zhejiang Colon Cancer Database (1x) and was not identified in MutDB. The variant was identified in control databases in 489 (3 homozygous) of 277224 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 440 (3 homozygous) of 24030 chromosomes (freq: 0.02), Other in 4 of 6464 chromosomes (freq: 0.0006), Latino in 32 of 34420 chromosomes (freq: 0.0009), European Non-Finnish in 12 of 126714 chromosomes (freq: 0.0001), East Asian in 1 of 18868 chromosomes (freq: 0.00005); it was not observed in the Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Lys18 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Arg impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	May 13, 2019	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PALB2: BS1, BS2 -

Hereditary cancer-predisposing syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 25, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

Familial cancer of breast

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
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	Invitae	Feb 01, 2024	- -

Fanconi anemia complementation group N

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely 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

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0083

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

0.71

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.039

D;.

Polyphen

1.0

D;.

Vest4

0.52

MVP

0.71

MPC

0.32

ClinPred

0.041

GERP RS

5.5

Varity_R

0.46

gMVP

0.031

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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