16-23623062-G-C

Variant summary

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

The NM_024675.4(PALB2):ā€‹c.2903C>Gā€‹(p.Ala968Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000013 ( 0 hom. )

Consequence

PALB2
NM_024675.4 missense

Scores

1
9
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1O:1

Conservation

PhyloP100: 6.05
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]

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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.2903C>G p.Ala968Gly missense_variant 9/13 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.2903C>G p.Ala968Gly missense_variant 9/131 NM_024675.4 ENSP00000261584.4 Q86YC2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152108
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251472
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.000163
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461806
Hom.:
0
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
727214
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:
0.0000171
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152108
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 968 of the PALB2 protein (p.Ala968Gly). This variant is present in population databases (rs369132015, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, and/or suspected Lynch syndrome (PMID: 22241545, 25980754, 28767289, 30303537). ClinVar contains an entry for this variant (Variation ID: 126695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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, no assertion criteria providedcurationLeiden Open Variation DatabaseMay 13, 2019Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 25, 2024- -
not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 06, 2020Variant summary: PALB2 c.2903C>G (p.Ala968Gly) results in a non-conservative amino acid change located in the 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 2e-05 in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2903C>G has been reported in the literature in individuals with breast cancer (example, Tischkowitz_2012, Girard_2019), as a VUS in individuals undergoing Lynch syndrome testing (Yurgelun_2015), as a VUS in an individual with PDAC (Shindo_2017) These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5, likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 19, 2022This missense variant replaces alanine with glycine at codon 968 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 structural modeling study has predicted that this variant may affect PALB2 protein structure (PMID: 34092963). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with breast cancer (PMID: 22241545, 29522266, 30303537), in one individual affected with pancreatic cancer (PMID: 28767289) and one individual each affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large breast cancer case-control study, this variant has been observed in 2/60464 cases and 2/53459 controls (OR=0.884 (95%CI 0.125 to 6.277); p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010132). This variant has been identified in 8/282862 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 submitterclinical testingAmbry GeneticsJun 07, 2023The p.A968G variant (also known as c.2903C>G), located in coding exon 9 of the PALB2 gene, results from a C to G substitution at nucleotide position 2903. The alanine at codon 968 is replaced by glycine, an amino acid with similar properties. This variant has been detected in multiple breast cancer cohorts (Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439), but has also been identified in a cohort of control patients without breast cancer (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration has also been identified in pancreatic cancer patients undergoing multigene panel testing (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14). This amino acid position is well 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. -
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 09, 2019This variant is associated with the following publications: (PMID: 28767289, 22241545, 25980754, 30303537) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 31, 2023In the published literature, this variant has been reported in individuals with breast cancer (PMID: 22241545 (2012), 29522266 (2018), 30303537 (2019)), ovarian cancer (PMID: 2546565 (2021)), pancreatic cancer (PMID: 32659497 (2020), 28767289 (2017)) and a Lynch syndrome associated cancer (PMID: 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in breast cancer cases as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.000054 (7/129178 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. -
PALB2-related disorder Uncertain:1Other:1
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpreted as Uncertain significance and reported on 12-04-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 25, 2024The PALB2 c.2903C>G variant is predicted to result in the amino acid substitution p.Ala968Gly. This variant has been reported in single cases of pancreatic ductal adenocarcinoma, Lynch syndrome, and breast cancer (Shindo et al. 2017. PubMed ID: 28767289; Yurgelun et al. 2015. PubMed ID: 25980754; Tischkowitz et al. 2012. PubMed ID: 22241545; Girard et al. 2019. PubMed ID: 30303537, Table S3). However, the c.2903C>G variant was interpreted as uncertain in one report (Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126695/). 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
0.23
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.35
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T;T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.018
T
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Benign
-0.94
T
MutationAssessor
Uncertain
2.6
.;M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Benign
0.095
Sift
Uncertain
0.013
D;D
Sift4G
Uncertain
0.048
D;D
Polyphen
0.88
.;P
Vest4
0.64
MVP
0.58
MPC
0.31
ClinPred
0.72
D
GERP RS
5.8
Varity_R
0.57
gMVP
0.55

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.

Other links and lift over

dbSNP: rs369132015; hg19: chr16-23634383; API