chr16-23603592-A-T

Position:

chr16-23603592-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_024675.4(PALB2):c.3428T>A(p.Leu1143His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,614,046 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:5

Conservation

PhyloP100: 3.27

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 Likely_benign. Variant got -1 ACMG points.

BP6

Variant 16-23603592-A-T is Benign according to our data. Variant chr16-23603592-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126740.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=11, Benign=1}. Variant chr16-23603592-A-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3428T>A	p.Leu1143His	missense_variant	13/13	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.3428T>A	p.Leu1143His	missense_variant	13/13	1	NM_024675.4	ENSP00000261584.4		Q86YC2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251470

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000155

AC:

227

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

125

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2024	Published functional studies demonstrate minimal to no impact on protein abundance and activity (PMID: 31757951); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33558524, 24448499, 24556926, 26343384, 25186627, 26898890, 26689913, 31422574, 22692731, 20852946, 26283626, 25479140, 26564480, 27067391, 26315354, 27099641, 27878467, 21618343, 29522266, 30455982, 31512090, 34426522, 33630411, 33471991, 33980423, 32658311, 30306255, 33195396, 31451522, 35264596, 31206626, 28944238, 28779002, 20871615, 19609323, 24485656, 36672847, 36605468, 31757951, 34478935, 38918649, 34326862, 39541563) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 04, 2024	The PALB2 c.3428T>A (p.Leu1143His) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 20852946 (2010), 22692731 (2012), 24556926 (2014), 25186627 (2015), 26283626 (2015), 26315354 (2015), 26564480 (2015), 26898890 (2016), 28779002 (2017), 31206626 (2019), 31512090 (2019), 32658311 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), 33558524 (2021), 33980423 (2021), 36605468 (2023)), pancreatic cancer (PMID: 25479140 (2015)), pediatric low-grade gliomas (PMID: 33320972 (2020)), and colorectal cancer (PMID: 33630411 (2021)). This variant has also been identified in reportedly healthy individuals (PMID: 24556926 (2014), 26315354 (2015), 28779002 (2017), 32658311 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). A functional study using mammalian cells indicated this variant caused a reduction in DNA repair activity, but not resistance to cisplatin, a DNA cross linking agent (PMID: 31757951 (2019)). The frequency of this variant in the general population, 0.00026 (34/129188 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 06, 2016	- -

Familial cancer of breast

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 31, 2023	This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	case-control	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	Jun 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 15, 2021	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3428T>A, in exon 13 that results in an amino acid change, p.Leu1143His. This sequence change has been described in gnomAD with a low population frequency of 0.016% (dbSNP rs62625284). The p.Leu1143His change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is \ known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu1143His substitution. This sequence change has been observed in multiple individuals with breast, ovarian, or pancreatic cancer, but has also been observed in normal controls (PMID: 27878467; 25479140; 26315354; 26283626; 21618343). Another variant affecting the same codon, p.Leu1143Pro has been reported in an individual with bilateral breast cancer. Functional studies demonstrated that the p.Leu143Pro disrupted the PALB2-RAD51C-BRCA2 complex indicating the functional importance of the Leu1143 residue (PMID:24141787, PMID:21618343). Due to the lack of sufficient evidences, the clinical significance of the p.Leu1143His change remains unknown at this time -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2024	Variant summary: PALB2 c.3428T>A (p.Leu1143His) results in a non-conservative amino acid change located in the partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251470 control chromosomes, predominantly at a frequency of 0.00027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016). c.3428T>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Balia_2010, Damiola_2015, Ramus_2015, Thompson_2015, Bonache_2018, Scarpitta_2019, Weitzel_2019, Akcay_2021, Dorling_2021, Moradian_2021, Solmaz_2021, Subasioglu_2023), but it was also detected in unaffected controls (e.g. Akcay_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (SDHB c.269G>A, p.Arg90Gln; MLH1 c.676C>T, p.Arg226X; Ferrer-Avargues_2021, Moradian_2021). Experimental evidence evaluating an impact on protein function demonstrated the variant had 70% homologous recombination efficiency compared to wild-type and similar relative resistance to PARPi with wild-type (Boonen_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 20852946, 30306255, 33195396, 22692731, 26564480, 33471991, 33630411, 33558524, 26315354, 31512090, 33980423, 26283626, 31206626, 36605468). ClinVar contains an entry for this variant (Variation ID: 126740). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

PALB2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The PALB2 c.3428T>A variant is predicted to result in the amino acid substitution p.Leu1143His. This variant has been reported in patients with breast and/or ovarian cancer (Catucci et al. 2012. PubMed ID: 22692731; Balia et al. 2010. PubMed ID: 20852946; Moradian et al. 2021. PubMed ID: 33558524; Scarpitta et al. 2019. PubMed ID: 31512090; Hellebrand et al. 2011. PubMed ID: 21618343). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and it is listed in ClinVar with conflicting interpretations of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126740/). Functional studies have been inconclusive on the impact of this variant on protein function (Park et al. 2014. PubMed ID: 24141787; Boonen et al. 2019. PubMed ID: 31757951). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

bilateral breast cancer

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Apr 08, 2020

ACMG Guidelines 2015 criteria This variant is in exon 8 of the PALB2 gene, which is involved in repairing double-strand DNA breaks in WD40 repeat-like (V872- 1185 aa) domain, which serves as platforms for the assembly of protein complexes (e.g., BRCA1 / RAD51) or mediators of transient interplay among other proteins. This variant is in a hotspot of 12 pathogenic nonsense and frameshift variants, including one mutation (i.e., c.3426dupA; p.Leu1143Thrfs) at the same position (Source ClinVar) (PM1 Pathogenic Moderate). It has been reported in several cancers including breast cancers (PMID: 27878467; 25479140; 26315354; 26283626; 21618343). Furthermore, it has been experimentally shown that this missense change modestly reduces DNA double-stranded break-induced homologous recombination, affects the PALB2 protein interaction with RAD51C, XRCC3 and BRCA2 proteins and moderately increases cellular sensitivity to ionizing radiation (PMID: 24141787). 6 pathogenic predictions from EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT vs 5 benign predictions from DANN, DEOGEN2, MVP, PrimateAI and REVEL support its deleterious effect (PP3 Pathogenic Supporting). This variant was found in a 46-years old female with bilateral breast cancer and no reported family history of cancer. In summary, the available evidence is currently insufficient to determine the role of this variant in the disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.065

T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

2.0

.;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

.;D

Vest4

0.60

MVP

0.72

MPC

0.38

ClinPred

0.18

GERP RS

5.8

Varity_R

0.62

gMVP

0.37

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