GeneBe

rs45566737

Positions:

Variant summary

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

The NM_024675.4(PALB2):ā€‹c.3449T>Gā€‹(p.Leu1150Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000043 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 4.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PALB2NM_024675.4 linkuse as main transcriptc.3449T>G p.Leu1150Arg missense_variant 13/13 ENST00000261584.9 NP_078951.2 Q86YC2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PALB2ENST00000261584.9 linkuse as main transcriptc.3449T>G p.Leu1150Arg missense_variant 13/131 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152204
Hom.:
0
Cov.:
32
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:
0.0000199
AC:
5
AN:
251472
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
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:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000431
AC:
63
AN:
1461860
Hom.:
0
Cov.:
31
AF XY:
0.0000371
AC XY:
27
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000549
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
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
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingCounsylApr 07, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 31, 2023This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJan 22, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 14, 2022This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1150 of the PALB2 protein (p.Leu1150Arg). This variant is present in population databases (rs45566737, gnomAD 0.007%). This missense change has been observed in individual(s) with breast, endometrial, or colorectal cancer (PMID: 17200668, 26283626, 27443514, 27978560). ClinVar contains an entry for this variant (Variation ID: 141936). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 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. -
Uncertain significance, criteria provided, single submittercase-controlCancer Genetics Laboratory, Peter MacCallum Cancer CentreJun 01, 2015- -
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submittercurationSema4, Sema4May 20, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 16, 2024The p.L1150R variant (also known as c.3449T>G), located in coding exon 13 of the PALB2 gene, results from a T to G substitution at nucleotide position 3449. The leucine at codon 1150 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been previously reported in individuals with a personal and/or family history of breast cancer (Rahman N et al. Nat. Genet., 2007 Feb;39:165-7; Thompson ER et al. Breast Cancer Res., 2015 Aug;17:111). In addition, this variant has been reported in individuals diagnosed with colon and/or endometrial cancer (Ring KL et al. Mod. Pathol., 2016 11;29:1381-1389; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This alteration was also found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 14, 2022This missense variant replaces leucine with arginine at codon 1150 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 has reported the mutant protein to exhibit normal homology-directed DNA repair function in PALB2-deficient cells (PMID: 31636395). This variant has been reported in two individuals affected with breast cancer (PMID: 17200668, 26283626), one individual with endometrial carcinoma (PMID: 27443514) and two individuals with colorectal cancer (PMID: 27978560). This variant has been identified in 5/251472 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. -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 11, 2022Variant summary: PALB2 c.3449T>G (p.Leu1150Arg) 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 1.9e-05 in 257636 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3449T>G has been reported in the literature as a VUS in settings of multigene panel testing among individuals with a variety of cancers such as breast, endometrial and colon (example, Thompson_2015, Rahman_2007, Ring_2016, Pearlman_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Wiltshire_2019 cited in Boonen_2019). These results showed no damaging effect of this variant on homology directed repair (HDR). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoAug 18, 2023In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 26283626 (2015), 17200668 (2007)), endometrial cancer (PMID: 27443514 (2016)), and colorectal cancer (PMID: 27978560 (2017)). Functional evidence reports the variant does not disrupt homology-directed repair (HDR) (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.000035 (4/113754 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, criteria provided, single submitterclinical testingGeneDxJul 10, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate homology-directed repair comparable to wild-type (Wiltshire et al., 2020); This variant is associated with the following publications: (PMID: 26283626, 27443514, 27978560, 19609323, 20871615, 24485656, 31636395) -
PALB2-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 25, 2024The PALB2 c.3449T>G variant is predicted to result in the amino acid substitution p.Leu1150Arg. This variant has been reported in patients with cancer; however, functional studies thus far have not demonstrated an altered protein function, and no evidence confirms the pathogenicity of this variant (Wiltshire et al. 2020. PubMed ID: 31636395; Thompson et al. 2015. PubMed ID:26283626; Rahman et al. 2007. PubMed ID: 17200668; Ring et al. 2019. PubMed ID: 27443514; Pearlman et al. 2017. PubMed ID: 27978560). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. It is documented as a variant of uncertain significance by many labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/141936/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Benign
-0.20
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.057
T;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.83
T;T
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.63
D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
2.0
.;M
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-4.2
D;D
REVEL
Uncertain
0.29
Sift
Uncertain
0.0050
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
.;D
Vest4
0.75
MutPred
0.49
.;Gain of methylation at L1150 (P = 0.044);
MVP
0.69
MPC
0.37
ClinPred
0.77
D
GERP RS
5.8
Varity_R
0.83
gMVP
0.50

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.

Other links and lift over

dbSNP: rs45566737; hg19: chr16-23614892; API