chr16-23629775-G-A
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_024675.4(PALB2):c.2379C>T(p.Gly793Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,614,066 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )
Consequence
PALB2
NM_024675.4 synonymous
NM_024675.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.417
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 Likely_benign. Variant got -1 ACMG points.
BP6
Variant 16-23629775-G-A is Benign according to our data. Variant chr16-23629775-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128130.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=4, Benign=2}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.2379C>T | p.Gly793Gly | synonymous_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.2379C>T | p.Gly793Gly | synonymous_variant | 5/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251424Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135884
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GnomAD4 exome AF: 0.0000862 AC: 126AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 62AN XY: 727228
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GnomAD4 genome 0.0000854 AC: 13AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:2Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | May 15, 2022 | PALB2:c.2379C>T is present in 0.0081% in the large population studies (GnomAd). The deep exonic variant is predicted to create a de novo donor splice site in exon 5 by in silico splicing tools. Functional RNA study has shown that the variant causes an insignificant splicing aberration leading to out-of-frame transcript (PMID: 35806449, 31642931). Therefore the variant was classified as likely benign (ACMG/AMP: BS3-Stand alone, BS1, PP3). - |
| Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
| Likely benign, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 16, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2018 | 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 | Jun 27, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 01, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 01, 2022 | Variant summary: PALB2 c.2379C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 donor site. However, these predictions have yet to be confirmed by functional studies. In contrast, one recently published functional study reported this variant among those with no impact on RNA splicing (Karam_2019). The authors considered the in-silico splicing predictions as a false positive evidence category and reported re-classifying this variant from a VUS to likely benign based on their study. The variant allele was found at a frequency of 7.4e-05 in 256744 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.4e-05 vs 0.00016), allowing no conclusion about variant significance. c.2379C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Catucci_2014, Damiola_2015, Thompson_2015, Borecka_2016, Decker_2017 etc.). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, this variant was found in four women in FLOSSIES database of cancer free women older than age 70, suggesting that the variant could be benignTo our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar classified as VUS (n=5), Likely Benign (n=6) and Benign (n=1). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PALB2: PP3, BS1:Supporting, BS3:Supporting - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2020 | This variant is associated with the following publications: (PMID: 26564480, 26283626, 24556926, 28779002, 31642931) - |
Fanconi anemia complementation group N Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
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.Gly793= variant was identified in 2 of 5146 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was not identified in 3996 control chromosomes from healthy individuals (Catucci 2014, Thompson 2015). The variant was also identified in dbSNP (ID: rs377626805) as "With other allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics and one clinical laboratory; as uncertain significance by five submitters), and in LOVD 3.0 (1x) database. The variant was identified in control databases in 22 of 277202 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24034 chromosomes (freq: 0.00004), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 3 of 34412 chromosomes (freq: 0.00009), European in 15 of 126706 chromosomes (freq: 0.0001), Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian, and Finnish, populations. The p.Gly793= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. - |
PALB2-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
DS_DG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at