rs45616636

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_024675.4(PALB2):c.3278T>C(p.Ile1093Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I1093V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 4.45

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_024675.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PALB2	NM_024675.4 linkuse as main transcript	c.3278T>C	p.Ile1093Thr	missense_variant	12/13	ENST00000261584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PALB2	ENST00000261584.9 linkuse as main transcript	c.3278T>C	p.Ile1093Thr	missense_variant	12/13	1	NM_024675.4	P1
	ENST00000561764.1 linkuse as main transcript	n.185+553A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000795

AC:

AN:

251486

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.0000312

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 08, 2023	The p.I1093T variant (also known as c.3278T>C), located in coding exon 12 of the PALB2 gene, results from a T to C substitution at nucleotide position 3278. The isoleucine at codon 1093 is replaced by threonine, an amino acid with similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 0/1189 controls. (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This alteration was also reported in 1/1250 probands from the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54). In one study, this alteration was identified in 0/923 familial breast cancer cases and 1/1084 controls (Rahman N et al. Nat Genet, 2007 Feb;39:165-7). In one functional study, this alteration demonstrated normal PARP inhibitor sensitivity, BRCA1/BRCA2 binding, RAD51 foci formation and homology-directed DNA repair (HDR) (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This alteration was found to be hypomorphic in another homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 23, 2023	This missense variant replaces isoleucine with threonine at codon 1093 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported this variant protein to be normal in homology-mediated DNA repair, RAD51 foci formation, BRCA2 binding, survival to PARP inhibitor olaparib treatment, and subcellular localization (PMID: 31586400, 31636395). This variant has been reported in one individual in a breast cancer family registry (PMID: 25575445), an individual affected with unspecified advanced cancer (PMID: 28873162), and an unaffected control from a breast cancer case-control study (PMID: 17200668). This variant has been identified in 2/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 19, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	Published functional studies demonstrate no damaging effect: homology-directed repair, BRCA2 interaction, and nuclear localization similar to wildtype (Rodrigue 2019, Wiltshire 2019); Observed in individuals with personal or family history of breast cancer (Nguyen-Dumont 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 31586400, 25575445, 28873162, 31636395) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 28, 2023	In the published literature, this variant has been reported in individuals with unspecified cancers (PMIDs: 28873162 (2017) and 34326862 (2021)), as well as breast cancer (PMID: 25575445 (2015)). In addition, functional studies have shown that this variant results in normal HDR activity, PARP inhibitor olaparib sensitivity, and BRCA2 binding (PMIDs: 31586400 (2019) and 31636395 (2020)). The frequency of this variant in the general population, 0.000008 (2/251486 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PALB2 p.Ile1093Thr variant was identified in 1 of 2480 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer (Nguyen Dumont 2015). The variant was also identified in dbSNP (ID: rs45616636) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, in ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, Color Genomics), MutDB, and the Zhejiang University Database. The variant was not identified in the Cosmic, or LOVD 3.0 databases. The variant was identified in control databases in 2 of 246268 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 33582 chromosomes (freq: 0.00003), and European in 1 of 111718 chromosomes (freq: 0.00001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ile1093 residue is not conserved in mammals and other organisms, and 3 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein, although this is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1093 of the PALB2 protein (p.Ile1093Thr). This variant is present in population databases (rs45616636, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25575445, 34326862). ClinVar contains an entry for this variant (Variation ID: 182774). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400, 31636395). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Breast-ovarian cancer, familial, susceptibility to, 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Medical and Surgical Sciences, University of Bologna

Found in trans with a known pathogenic variant in a woman with triple-negative breast cancer at 53 years old and previous melanoma at 44, with no signs of Fanconi Anemia. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

0.0043

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.062

T;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.78

MutationTaster

Benign

0.73

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

D;D

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

.;D

Vest4

0.88

MutPred

0.47

.;Loss of stability (P = 0.0339);

MVP

0.77

MPC

0.21

ClinPred

0.94

GERP RS

6.1

Varity_R

0.58

gMVP

0.38

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