16-23603525-C-T
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_024675.4(PALB2):c.3495G>A(p.Ser1165Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,960 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 0 hom. )
Consequence
PALB2
NM_024675.4 synonymous
NM_024675.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.209
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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
Variant 16-23603525-C-T is Benign according to our data. Variant chr16-23603525-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 126745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23603525-C-T is described in Lovd as [Likely_benign]. Variant chr16-23603525-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.209 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.3495G>A | p.Ser1165Ser | synonymous_variant | 13/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.3495G>A | p.Ser1165Ser | synonymous_variant | 13/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes 0.00114 AC: 173AN: 151990Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000620 AC: 156AN: 251484Hom.: 0 AF XY: 0.000647 AC XY: 88AN XY: 135916
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GnomAD4 exome AF: 0.00142 AC: 2070AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.00138 AC XY: 1000AN XY: 727232
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GnomAD4 genome 0.00114 AC: 173AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84AN XY: 74354
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:25
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:11
| Likely benign, 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, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 24, 2022 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 18, 2016 | Variant summary: The c.3495G>A variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however, it may strengthen a cryptic 5' splicing donor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 89/125390 control chromosomes at a frequency of 0.0007098, which is about 5 times of the maximal expected frequency of a pathogenic allele (0.0001563), suggesting this variant is benign. In addition, mutliple clinical laboratories/reputable databases/literatures classified this variant as benign/polymorphism. Taken together, this variant was classified as benign. - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | PALB2: BP4, BP7 - |
| Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 13, 2019 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Hereditary cancer-predisposing syndrome Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2014 | 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. - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 21, 2015 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 23, 2021 | - - |
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 03, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 25, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Fanconi anemia complementation group N Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Ser1165Ser variant was identified in 19 of 8732 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 11 of 4896 control chromosomes (frequency: 0.002) from healthy individuals (Papi_2010_19763884, Ding_2011_20927582, Bogdanova_2011_21165770, Hellebrand_2011_21618343, Nguyen-Dumont_2013_24206657, Thompson_2015_26283626, Aoude_2014_24949998, Zhen_2015_25356972). The variant was also identified in dbSNP (ID: rs45439097) as “With other allele”, ClinVar (2x as benign by GeneDx, Invitae, 5x as likely benign by Ambry Genetics, Prevention Genetics, Illumina Clinical services, Quest Diagnostics, PALB2 database), Clinvitae (4x, as benign and likely benign by ClinVar), LOVD 3.0 (6x reported) and Zhejiang Colon Cancer Database (1x. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 192 of 277176 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 29 of 24016 chromosomes (freq: 0.0012), other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 11 of 34420 chromosomes (freq: 0.0003), European Non-Finnish in 149 of 126698 chromosomes (freq: 0.0012), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition the variant was identified by our laboratory in 1 individual with breast and skin cancer with a co-occurring pathogenic BRCA2 variant (c.8904delC p.Val2969CysfsX7), increasing the likelihood that the p.Ser1165Ser variant does not have clinical significance. The p.Ser1165Ser 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Familial cancer of breast Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | May 15, 2022 | PALB2:c.3495G>A is present in 0.070% in the large population studies (GnomAd). The deep exonic variant is predicted to create a de novo donor splice site in the last exon (exon 13) of PALB2 by in silico splicing tools. Functional RNA study has shown that the variant does not cause splicing aberration (PMID: 35806449). Therefore the variant was classified as likely benign (ACMG/AMP: BS3-Stand alone, BS1, PP3). - |
PALB2-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 02, 2024 | 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). - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 26, 2023 | - - |
Malignant tumor of breast Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Ser1165Ser variant was identified in 19 of 8732 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 11 of 4896 control chromosomes (frequency: 0.002) from healthy individuals (Papi_2010_19763884, Ding_2011_20927582, Bogdanova_2011_21165770, Hellebrand_2011_21618343, Nguyen-Dumont_2013_24206657, Thompson_2015_26283626, Aoude_2014_24949998, Zhen_2015_25356972). The variant was also identified in dbSNP (ID: rs45439097) as “With other allele”, ClinVar (2x as benign by GeneDx, Invitae, 5x as likely benign by Ambry Genetics, Prevention Genetics, Illumina Clinical services, Quest Diagnostics, PALB2 database), Clinvitae (4x, as benign and likely benign by ClinVar), LOVD 3.0 (6x reported) and Zhejiang Colon Cancer Database (1x. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 192 of 277176 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 29 of 24016 chromosomes (freq: 0.0012), other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 11 of 34420 chromosomes (freq: 0.0003), European Non-Finnish in 149 of 126698 chromosomes (freq: 0.0012), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition the variant was identified by our laboratory in 1 individual with breast and skin cancer with a co-occurring pathogenic BRCA2 variant (c.8904delC p.Val2969CysfsX7), increasing the likelihood that the p.Ser1165Ser variant does not have clinical significance. The p.Ser1165Ser 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at