rs756502783
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The ENST00000261584.9(PALB2):c.2505C>T(p.Ser835=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,834 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). Synonymous variant affecting the same amino acid position (i.e. S835S) has been classified as Likely benign.
Frequency
Consequence
ENST00000261584.9 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2505C>T | p.Ser835= | 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.2505C>T | p.Ser835= | synonymous_variant | 5/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250864Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135730
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461680Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727152
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 07, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2019 | This variant is associated with the following publications: (PMID: 30287823) - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
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. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 20, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2024 | 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 | Aug 12, 2020 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | PALB2, EXON5, c.2505C>T, p.Ser835Ser, Heterozygous, Likely Benign The PALB2 p.Ser835= variant was identified in the literature in 1 of 24,980 control chromosomes from healthy individuals (frequency: 0.00008) in a large population study and was not identified in an affected population (Momozawa 2018). The variant was identified in dbSNP (rs756502783) as “with likely benign, other allele”, ClinVar (classified as likely benign by Invitae, GeneDx and 2 others; and as uncertain significance by EGL diagnostics) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 2 of 245,838 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15,300 chromosomes (freq: 0.00006) and European in 1 of 111,350 chromosomes (freq: 0.000009), but not in the “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser835= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not a conserved nucleotide. In addition, the variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. Assessment Date: 2019/07/23 References (PMIDs): 30287823 - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at