Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000203860 | SCV000260501 | uncertain significance | Familial cancer of breast | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 76 of the PALB2 protein (p.Ile76Val). This variant is present in population databases (rs541028076, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 18053174, 34326862). This variant is also known as c.5038A>G. ClinVar contains an entry for this variant (Variation ID: 220168). 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 valine 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). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. |
Ambry Genetics | RCV000223229 | SCV000276958 | likely benign | Hereditary cancer-predisposing syndrome | 2017-10-30 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Gene |
RCV000590079 | SCV000565341 | uncertain significance | not provided | 2022-02-14 | criteria provided, single submitter | clinical testing | Observed in an individual with breast cancer and in an unaffected control (Foulkes 2007, Ramus 2015); Published functional studies are conflicting: BRCA1 interaction and PARP inhibitor response was inconclusive while cell survival in response to olaparib was comparable to wild type (Rodrigue 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18053174, 26315354, 29522266, 33195396, 34298626, 20871615, 19369211, 31586400) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001526861 | SCV000699558 | uncertain significance | not specified | 2021-05-19 | criteria provided, single submitter | clinical testing | Variant summary: PALB2 c.226A>G (p.Ile76Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. A recently published study evaluated this variant across three in-silico prediction algorithms, namely VEST3.0, M-CAP and REVEL and all three predicted a probably neutral/likely benign outcome (Rodriguez_2019). The variant allele was found at a frequency of 3.4e-05 in 263022 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.226A>G has been reported in the literature in at-least one individual affected with early onset breast cancer or familial breast cancer in a study that was limited to screening for coding exons in the PALB2 gene (example, Foulkes_2007). In another report, it was identified in an unaffected control (example, Ramus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an experimental system that evaluated sensitivity to PARP inhibitor, Olaparib and the impact of PALB2 variants on BRCA1 and BRCA2 interaction by mammalian two-hybrid assay (Rodriguez_2019). The results of this functional study were internally consistent with the predictions from in-silico algorithms mentioned above. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
Color Diagnostics, |
RCV000223229 | SCV000902947 | likely benign | Hereditary cancer-predisposing syndrome | 2016-12-22 | criteria provided, single submitter | clinical testing | |
Leiden Open Variation Database | RCV001030134 | SCV001192949 | uncertain significance | Carcinoma of colon | 2017-01-31 | no assertion criteria provided | curation | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Melissa DeRycke. |