rs150390726

Positions:

chr16-23641135-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_024675.4(PALB2):c.23C>T(p.Pro8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,342 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P8S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 1.98

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 Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 14 uncertain in NM_024675.4

BP4

Computational evidence support a benign effect (MetaRNN=0.017316192).

BP6

Variant 16-23641135-G-A is Benign according to our data. Variant chr16-23641135-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126652.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2, Benign=1}. Variant chr16-23641135-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/13	1	NM_024675.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000125

AC:

AN:

247906

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

134434

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461170

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.000201

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000480

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000559

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2017	Variant summary: The c.23C>T (p.Pro8Leu) in PALB2 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant is located in the a coiled-coil domain of PALB2 required for RAD51- and BRCA1-binding, however no functional studies confirming deleterious effect of this change have been reported at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.0001801 (20/ 111058 chrs tested), predominantly in individuals of African descent (0.001817; 16/ 8808 chrs tested). The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.000156, suggesting it is may be an ethnic-specific functional polymorphism. The variant has been reported in BrC pt without strong evidence for causality. The variant is cited as VUS/Likely Benign by reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was 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	Mendelics	Dec 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2020	Published functional studies demonstrate moderate PARPi sensitivity, moderate interaction with BRCA1, cellular localization similar to wild type, normal response to DNA damage, reduced RAD51 foci formation, and normal or decreased HDR activity (Rodrigue 2019, Wiltshire 2019); 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: 32185139, 33169439, 32209438, 31636395, 31658756, 31586400, 23555315, 25503501, 28944238, 28528518, 26315354, 25186627, 21113654) -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 12, 2020	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	curation	Sema4, Sema4	Apr 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2016	- -

PALB2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

The PALB2 c.23C>T variant is predicted to result in the amino acid substitution p.Pro8Leu. This variant has been reported in individuals with breast and colorectal cancer; however, a causative association has not been established (Ding et al. 2011. PubMed ID: 21113654; Tung et al. 2014. PubMed ID: 25186627, Supplemental Table 2; Maxwell et al. 2014. PubMed ID: 25503501, Supplemental Table 1; Cock-Rada et al. 2018. PubMed ID: 28528518, Table 2; DeRycke et al. 2017. PubMed ID: 28944238, Supplemental Table S2). Functional studies of this variant are conflicting, with some indicating similar function to wild type protein (Rodrigue et al. 2019. PubMed ID: 31586400). This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23652456-G-A). ClinVar classifications range from likely benign to uncertain, with a consensus of recent classifications pointing toward likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126652/). Although we suspect this alteration is more likely benign, at this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.66

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.31

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.74

M_CAP

Benign

0.012

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.95

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.056

Sift

Uncertain

0.014

Sift4G

Benign

0.14

Polyphen

0.0080

Vest4

0.11

MVP

0.42

MPC

0.27

ClinPred

0.077

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.026

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