ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2928G>T (p.Arg976Ser)

gnomAD frequency: 0.00001  dbSNP: rs878855115
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000556190 SCV000633392 uncertain significance Familial cancer of breast 2023-06-22 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function. ClinVar contains an entry for this variant (Variation ID: 460971). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 976 of the PALB2 protein (p.Arg976Ser).
Color Diagnostics, LLC DBA Color Health RCV000777238 SCV000912929 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter clinical testing This missense variant replaces arginine with serine at codon 976 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Ambry Genetics RCV000777238 SCV001178610 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-29 criteria provided, single submitter clinical testing The p.R976S variant (also known as c.2928G>T), located in coding exon 9 of the PALB2 gene, results from a G to T substitution at nucleotide position 2928. The arginine at codon 976 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV002298647 SCV002588292 uncertain significance not provided 2022-04-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003444569 SCV004171460 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 5 2023-09-26 criteria provided, single submitter clinical testing The PALB2 c.2928G>T (p.Arg976Ser) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with hereditary breast and ovarian cancer or 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.
Baylor Genetics RCV000556190 SCV004202194 uncertain significance Familial cancer of breast 2023-06-22 criteria provided, single submitter clinical testing

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