rs62625272
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001407304.1(PALB2):c.-692C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,612,258 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
Consequence
NM_001407304.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.194C>T | p.Pro65Leu | missense_variant | 3/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.194C>T | p.Pro65Leu | missense_variant | 3/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251470Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135906
GnomAD4 exome AF: 0.0000596 AC: 87AN: 1460128Hom.: 0 Cov.: 31 AF XY: 0.0000592 AC XY: 43AN XY: 726490
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74320
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:6Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 26, 2024 | The PALB2 c.194C>T (p.Pro65Leu) missense change has a maximum subpopulation frequency of 0.009% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, and a functional study supports that this variant does not substantially impact protein function (PMID: 31586400). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 15, 2018 | - - |
Uncertain significance, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 65 of the PALB2 protein (p.Pro65Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast, ovarian, and/or pancreatic cancer (PMID: 20582465, 25356972, 26315354, 26564480, 35264596). This missense change has been observed to co-occur in individuals with a different variant in PALB2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 128124). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:2Benign:5
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | PALB2: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2024 | Observed in individuals with PALB2-related and other cancers, but also in healthy controls (PMID: 20582465, 25356972, 26564480, 26315354, 26283626, 25980754, 28779002, 29522266, 32546565, 35264596, 36605468); Published functional studies suggest no damaging effect: PARP inhibitor sensitivity and BRCA1 interaction comparable to wild type (PMID: 31586400); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20582465, 24728327, 25356972, 26283626, 26564480, 25980754, 28779002, 26315354, 29522266, 33471991, 32546565, 20871615, 19369211, 35264596, 36605468, 31586400, 34326862) - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 20, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
not specified Uncertain:1Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2023 | Variant summary: PALB2 c.194C>T (p.Pro65Leu) 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 4.8e-05 in 251470 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. However, the variant was observed in the North-western European subpopulation with an even higher allele frequency, 0.00017 (i.e. 7/42220 alleles), and this frequency is similar to the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), suggesting that the variant might be a benign polymorphism. The variant, c.194C>T, has been reported in the literature in individuals affected with breast cancer and other tumor phenotypes, however it was also reported in several healthy controls (e.g. Adank_2011, Bodian_2014, Zhen_2015, Yurgelun_2015, Thompson_2015, Ramus_2015, Damiola_2015, Decker_2017, Hauke_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. However, in a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 12/60466 cases, but was also found in 11/53461 controls, suggesting no increased relative risk for breast cancer development (Dorling_2021 through LOVD). In addition, at least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had BRCA1-binding similar to wild-type, and had normal function in a drug sensitivity (PARP inhibitor) assay (Rodrigue_2019). The following publications have been ascertained in the context of this evaluation (PMID: 20582465, 24728327, 26564480, 33471991, 29522266, 33139182, 26315354, 31586400, 26283626, 25980754, 25356972, 35264596, 28779002). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and VUS (n=11). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 03, 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 22, 2015 | - - |
Pancreatic cancer, susceptibility to, 3 Uncertain:1
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at