Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781693 | SCV000919949 | uncertain significance | not specified | 2018-08-27 | criteria provided, single submitter | clinical testing | Variant summary: PALB2 c.3066G>A (p.Met1022Ile) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 277206 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3066G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV001018406 | SCV001179640 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-29 | criteria provided, single submitter | clinical testing | The p.M1022I variant (also known as c.3066G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3066. The methionine at codon 1022 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001299914 | SCV001489030 | uncertain significance | Familial cancer of breast | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1022 of the PALB2 protein (p.Met1022Ile). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 633345). 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 not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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. |
| Baylor Genetics | RCV001299914 | SCV005053939 | uncertain significance | Familial cancer of breast | 2023-12-15 | criteria provided, single submitter | clinical testing |