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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PALB2
ENST00000261584.9 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: -0.649
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BP6
Variant 16-23629649-G-A is Benign according to our data. Variant chr16-23629649-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197859.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}.
BP7
Synonymous conserved (PhyloP=-0.649 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PALB2NM_024675.4 linkuse as main transcriptc.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
PALB2ENST00000261584.9 linkuse as main transcriptc.2505C>T p.Ser835= synonymous_variant 5/131 NM_024675.4 ENSP00000261584 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250864
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135730
show subpopulations
Gnomad AFR exome
AF:
0.0000621
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1461680
Hom.:
0
Cov.:
32
AF XY:
0.0000165
AC XY:
12
AN XY:
727152
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:3
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 07, 2015- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 07, 2019This variant is associated with the following publications: (PMID: 30287823) -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Uncertain significance, no assertion criteria providedcurationLeiden Open Variation DatabaseAug 25, 2018Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 20, 2018- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 26, 2024This 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 submittercurationSema4, Sema4Aug 12, 2020- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 27, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.76
CADD
Benign
2.3
DANN
Benign
0.61

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: rs756502783; hg19: chr16-23640970; API