rs911713488
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_024675.4(PALB2):c.828C>T(p.His276=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,986 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PALB2
NM_024675.4 synonymous
NM_024675.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.81
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=-0.9).
BP6
?
Variant 16-23635718-G-A is Benign according to our data. Variant chr16-23635718-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461024.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1}.
BP7
?
Synonymous conserved (PhyloP=-1.81 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.828C>T | p.His276= | synonymous_variant | 4/13 | ENST00000261584.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.828C>T | p.His276= | synonymous_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251410Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135886
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727232
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2016 | 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | May 10, 2021 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 17, 2021 | - - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2020 | - - |
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. - |
Familial ovarian cancer Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.His276= variant was not identified in the literature nor was it identified in the MutDB, LOVD 3.0, or the Zhejiang University Database. The variant was identified in dbSNP (ID: rs911713488) as “NA”, in ClinVar and Clinvitae (2x as likely benign by Invitae and Ambry Genetics) and Cosmic (1x as "neutral”, Confirmed somatic adenocarcinoma in prostate) databases. The variant was identified in control databases in 1 of 246200 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Specifically the variant was observed in the South Asian population in 1 of 30782 chromosomes (freq: 0.000032), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.His276= 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. However, this information is not predictive enough to rule out pathogenicity. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
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.His276= variant was not identified in the literature nor was it identified in the MutDB, LOVD 3.0, or the Zhejiang University Database. The variant was identified in dbSNP (ID: rs911713488) as “NA”, in ClinVar and Clinvitae (2x as likely benign by Invitae and Ambry Genetics) and Cosmic (1x as "neutral”, Confirmed somatic adenocarcinoma in prostate) databases. The variant was identified in control databases in 1 of 246200 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Specifically the variant was observed in the South Asian population in 1 of 30782 chromosomes (freq: 0.000032), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or Finnish populations. The p.His276= 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. However, this information is not predictive enough to rule out pathogenicity. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. - |
Familial cancer of breast Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | - - |
Computational scores
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Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at