ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2755G>A (p.Val919Ile)

gnomAD frequency: 0.00002  dbSNP: rs775193384
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre RCV000211057 SCV000268017 uncertain significance Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Ambry Genetics RCV000454132 SCV000538158 likely benign Hereditary cancer-predisposing syndrome 2024-04-29 criteria provided, single submitter clinical testing 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.
GeneDx RCV000478723 SCV000566709 uncertain significance not provided 2025-03-11 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer as well as unaffected controls (PMID: 26283626, 33471991); Published functional studies using a cellular homology directed DNA repair (HDR) assay do not demonstrate a damaging effect (PMID: 31636395); This variant is associated with the following publications: (PMID: 26283626, 33471991, 35762214, 31636395)
Color Diagnostics, LLC DBA Color Health RCV000454132 SCV000685975 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-22 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 919 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant has neutral impact on homology-directed DNA repair activity (PMID: 31636395). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010695). This variant has been identified in 4/249880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000211057 SCV000757149 uncertain significance Familial cancer of breast 2024-09-12 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 919 of the PALB2 protein (p.Val919Ile). This variant is present in population databases (rs775193384, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 225856). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31636395, 35762214). 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.
CeGaT Center for Human Genetics Tuebingen RCV000478723 SCV002545766 uncertain significance not provided 2022-05-01 criteria provided, single submitter clinical testing PALB2: PM2, BP4, BS3:Supporting
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465567 SCV002760824 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003150103 SCV003838710 uncertain significance Breast and/or ovarian cancer 2023-06-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005016571 SCV005646474 uncertain significance Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5 2024-02-05 criteria provided, single submitter clinical testing
Integrative Tumor Epidemiology Branch, National Institutes of Health RCV002266935 SCV002549702 uncertain significance Chordoma 2021-03-22 no assertion criteria provided research Modestly reduce HRR activity and BRCA2 binding

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.