rs139362268
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6_Very_StrongBP7
The NM_024675.4(PALB2):c.1881G>T(p.Val627=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,614,046 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V627V) has been classified as Benign.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000092 ( 0 hom. )
Consequence
PALB2
NM_024675.4 synonymous
NM_024675.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.605
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 -11 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
Variant 16-23630273-C-A is Benign according to our data. Variant chr16-23630273-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 126626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23630273-C-A is described in Lovd as [Likely_benign]. Variant chr16-23630273-C-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.605 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.1881G>T | p.Val627= | 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.1881G>T | p.Val627= | synonymous_variant | 5/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000135 AC: 34AN: 251104Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135868
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GnomAD4 exome AF: 0.0000917 AC: 134AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000921 AC XY: 67AN XY: 727238
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GnomAD4 genome 0.0000920 AC: 14AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:4
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Dec 08, 2022 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 12, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 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. - |
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2019 | Variant summary: PALB2 c.1881G>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 246196 control chromosomes, predominantly at a frequency of 0.0028 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 18-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1881G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Casadei_2011, Catucci_2012, Hofstatter_2011) with limited information (ie, lack of co-occurrence and cosegregation data). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 31, 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. - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | PALB2: BP4 - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 03, 2022 | - - |
Familial cancer of breast Benign:2
| 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. - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 26, 2021 | - - |
Carcinoma of colon Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Val627Val variant was identified in 2 of 378 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer (Hofstatter_2011_21365267, Catucci_2012_22692731). The variant was also identified in the following databases: dbSNP (ID: rs139362268) as “With Likely benign allele” ,ClinVar (2x as benign by GeneDx, Invitae, 4x as likely benign by Ambry Genetics, Color Genomics, Quest Diagnostics, Palb2 database), Clinvitae (3x as benign and likely benign by ClinVar), LOVD 3.0 (3x "probably does not affect function"). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 32 of 246196 chromosomes at a frequency of 0.00013 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 1 of 5482 chromosomes (freq: 0.00018), European Non-Finnish in 3 of 111674 chromosomes (freq: 0.00003), Ashkenazi Jewish in 28 of 9848 chromosomes (freq: 0.003), while the variant was not observed in the African, Latino, East Asian, European Finnish, and South Asian populations. The p.Val627Val 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 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. - |
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 | Dec 07, 2021 | - - |
Endometrial carcinoma Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Val627Val variant was identified in 2 of 378 proband chromosomes (frequency: 0.005) from individuals or families with breast cancer (Hofstatter_2011_21365267, Catucci_2012_22692731). The variant was also identified in the following databases: dbSNP (ID: rs139362268) as “With Likely benign allele” ,ClinVar (2x as benign by GeneDx, Invitae, 4x as likely benign by Ambry Genetics, Color Genomics, Quest Diagnostics, Palb2 database), Clinvitae (3x as benign and likely benign by ClinVar), LOVD 3.0 (3x "probably does not affect function"). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 32 of 246196 chromosomes at a frequency of 0.00013 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include other in 1 of 5482 chromosomes (freq: 0.00018), European Non-Finnish in 3 of 111674 chromosomes (freq: 0.00003), Ashkenazi Jewish in 28 of 9848 chromosomes (freq: 0.003), while the variant was not observed in the African, Latino, East Asian, European Finnish, and South Asian populations. The p.Val627Val 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 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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at