chr16-23630025-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The ENST00000261584.9(PALB2):c.2129C>T(p.Thr710Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T710A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
PALB2
ENST00000261584.9 missense
ENST00000261584.9 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 3.97
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.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in ENST00000261584.9
BP4
Computational evidence support a benign effect (MetaRNN=0.24672037).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.2129C>T | p.Thr710Met | missense_variant | 5/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.2129C>T | p.Thr710Met | missense_variant | 5/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251492Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727248
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | Aug 25, 2018 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2023 | Not 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; Observed in a pediatric patient with acute myeloid leukemia and in unaffected control subjects from two breast cancer cohorts where this variant was absent in breast cancer cases (Momozawa et al., 2018; Jeong et al., 2019; Weitzel et al., 2019); This variant is associated with the following publications: (PMID: 30287823, 22941656, 31470354, 31206626) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 16, 2023 | The frequency of this variant in the general population, 0.000012 (3/251492 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/PALB2), and in an individual with pediatric acute myeloid leukemia (AML) (PMID: 31470354 (2019)). It has also been reported in healthy individuals in large breast cancer association studies (PMID: 30287823 (2018), 31206626 (2019), 33471991 (2021), https://databases.lovd.nl/shared/variants/PALB2). 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. - |
Familial cancer of breast Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 710 of the PALB2 protein (p.Thr710Met). This variant is present in population databases (rs759024828, gnomAD 0.006%). This missense change has been observed in individual(s) with pediatric acute myeloid leukemia, breast cancer, biliary tract cancer, pancreatic ductal adenocarcinoma (PMID: 31206626, 31470354, 34326862, 35171259, 36243179). ClinVar contains an entry for this variant (Variation ID: 410177). 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%. 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 submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 01, 2023 | This missense variant replaces threonine with methionine at codon 710 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010448). This variant also has been reported in breast, pancreatic and prostate cancer case-control studies in which it was detected in 1 unaffected control in each study and absent in cancer cases (PMID: 30287823, 31214711, 32980694). This variant has been identified in 3/251492 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 | clinical testing | Ambry Genetics | Dec 20, 2022 | The p.T710M variant (also known as c.2129C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2129. The threonine at codon 710 is replaced by methionine, an amino acid with similar properties. In one study, this alteration was observed with an allele frequency of 0.0001 in 12490 male controls of Japanese ancestry, but not observed in 53 unselected male or 7051 unselected female breast cancer patients, or 11241 female controls (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration was detected in 1/5589 German and 1/1054 Hispanic BRCA1/2-negative probands with breast cancer but was not detected in controls (Hauke J et al. Cancer Med. 2018 Apr;7:1349-1358; Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836). 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 specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 08, 2021 | Variant summary: PALB2 c.2129C>T (p.Thr710Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2129C>T has been reported in the literature in unaffected control individuals of Japanese ancestry and a multiethnic cohort respectively in case control studies of individuals affected with Breast Cancer (example, Momozawa_2018, Weitzel_2019). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
PALB2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 06, 2024 | The PALB2 c.2129C>T variant is predicted to result in the amino acid substitution p.Thr710Met. This variant has been reported in individuals with breast cancer (Hauke et al. 2018. PubMed ID: 29522266; Bhai et al. 2021. PubMed ID: 34326862), acute myeloid leukemia (Jeong et al. 2019. PubMed ID: 31470354), and pancreatic cancer (Yin et al. 2022. PubMed ID: 35171259). However, this variant was also observed at similar frequencies in patients (0.0017%) and controls (0.0037%) in a large breast cancer risk-association study (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/410177/). 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 | Feb 25, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
MutPred
0.25
.;Loss of glycosylation at T710 (P = 0.0144);
MVP
0.65
MPC
0.35
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at