rs61756147
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_024675.4(PALB2):c.298C>T(p.Leu100Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00036 ( 0 hom. )
Consequence
PALB2
NM_024675.4 missense
NM_024675.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 0.0960
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 -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.020982713).
BP6
Variant 16-23636248-G-A is Benign according to our data. Variant chr16-23636248-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126698.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6, not_provided=2}. Variant chr16-23636248-G-A is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.298C>T | p.Leu100Phe | missense_variant | 4/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.298C>T | p.Leu100Phe | missense_variant | 4/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes 0.000197 AC: 30AN: 151936Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000163 AC: 41AN: 251306Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135828
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GnomAD4 exome AF: 0.000359 AC: 525AN: 1461716Hom.: 0 Cov.: 32 AF XY: 0.000351 AC XY: 255AN XY: 727154
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GnomAD4 genome 0.000197 AC: 30AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74336
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:7Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:5
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 08, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2022 | 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 | Dec 10, 2020 | - - |
| Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Jun 18, 2018 | - - |
| Benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 10, 2022 | - - |
not provided Uncertain:3Other:1
| Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. - |
| not provided, flagged submission | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2023 | Not found to have a statistically significant association with breast cancer risk in a multi-ethnic exome array study (Haiman et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24448499, 25479140, 26283626, 21409391, 26315354, 25225577, 25186627, 26976419, 27060149, 26689913, 28767289, 28779002, 32659497, 32546565, 28259476, 35263119, 30541756, 28873162, 32885271, 33471991, 20871615, 19369211, 23555315, 34326862) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 17, 2023 | The frequency of this variant in the general population, 0.00033 (42/129102 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 25225577 (2014), 26315354 (2015), 26976419 (2016), 28767289 (2017), and 28873162 (2017)). This variant has also been identified in healthy, unaffected individuals (PMIDs: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 26283626 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Familial cancer of breast Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Pancreatic cancer, susceptibility to, 3 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Leu100Phe variant was identified in 5 of 11930 proband chromosomes (frequency: 0.0004) from American, Canadian and Australian individuals or families with BRCA1/2 negative breast cancer, familial breast or breast/ovarian cancer, or ovarian cancer and was present in 4 of 10858 control chromosomes (frequency: 0.0003) from healthy individuals (Ramus_2015_26315354, Thompson_2015_26283626, Tung_2016_26976419, Wong_2011_21409391, Hartley_2014_25225577). The variant was identified in the following databases: dbSNP (ID: rs61756147) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Invitae, Ambry Genetics, Cancer Genetics Laboratory (Peter MacCallum Cancer Center) and the PALB2 database), Clinvitae (3x), LOVD 3.0 (1x), Zhejiang Colon Cancer Database (1x), and in control databases in 46 of 277092 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). Observation by population include “Other” in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34398 chromosomes (freq: 0.00003), European Non-Finnish in 42 of 126642 chromosomes (freq: 0.0003), and European Finnish in 2 of 25786 chromosomes (freq: 0.00008); it was not observed in the African, Ashkenazi Jewish, East Asian, and South Asian populations. The variant was not identified in Cosmic or MutDB. The p.Leu100 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the variant Phe impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance. - |
PALB2-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 05, 2024 | The PALB2 c.298C>T variant is predicted to result in the amino acid substitution p.Leu100Phe. This variant has been detected in patients with breast and ovarian cancer (Wong et al. 2011. PubMed ID: 21409391; Tung et al. 2016. PubMed ID: 26976419, Table A2; Hartley et al. 2014. PubMed ID: 25225577, Table S4; Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4; Kanchi et al. 2014. PubMed ID: 24448499, sup data 8) and pancreatic cancer (Shindo et al. 2017. PubMed ID: 28767289, referred to as c.298G>A; Grant et al. 2015. PubMed ID: 25479140, Sup. Table 1). However, it was detected in an equal number of cases and controls (2) in one of these studies (Ramus et al. 2015. PubMed ID: 26315354 Sup. Table 4). This variant is documented in the gnomAD general population database with a minor allele frequency of ~0.03% among non-Finnish Europeans and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126698/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Fanconi anemia complementation group N Uncertain:1
| Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 21, 2022 | - - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 09, 2023 | Variant summary: PALB2 c.298C>T (p.Leu100Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 293556 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, this variant has been also reported in 3/7325 European American women who were older than age 70 years and cancer free (in the FLOSSIES database). c.298C>T has been reported in the literature in individuals affected with different types of cancer (Wong 2011, Haiman 2013, Hartley 2014, Tung 2014, Grant 2015, Ramus 2015, Lu 2015, Shindo 2017, Seligson_2019), but was also found in healthy controls (Thompson 2015, Ramus 2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.5266dupC (p.Gln1756Profs*74), Tung 2014), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified as VUS (n=6), Likely Benign (n=5) and Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary cancer-predisposing syndrome;C1835817:Fanconi anemia complementation group N Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Uncertain significance and reported on 09-21-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at