Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000656941 | SCV000150012 | uncertain significance | not provided | 2022-06-13 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair comparable to wild-type (Wiltshire 2020); Observed in individuals with breast and other cancers as well as unaffected controls (Casadei 2011, Gonzalez-Garay 2013, Thompson 2015, Yurgelun 2015, Kim 2017, Momozawa 2018, Fujita 2020, Song 2021); This variant is associated with the following publications: (PMID: 21285249, 24082139, 26283626, 25980754, 27783279, 30287823, 32566746, 32546565, 27535533, 33309985, 31636395, 19609323, 20871615, 24485656) |
Ambry Genetics | RCV000116103 | SCV000185684 | likely benign | Hereditary cancer-predisposing syndrome | 2019-02-22 | 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. |
Invitae | RCV000114616 | SCV000255103 | likely benign | Familial cancer of breast | 2024-02-01 | criteria provided, single submitter | clinical testing | |
Cancer Genetics Laboratory, |
RCV000114616 | SCV000268025 | uncertain significance | Familial cancer of breast | 2015-06-01 | criteria provided, single submitter | case-control | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000656941 | SCV000601782 | likely benign | not provided | 2022-02-21 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000116103 | SCV000910839 | likely benign | Hereditary cancer-predisposing syndrome | 2015-01-29 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000212827 | SCV000917939 | likely benign | not specified | 2023-09-11 | criteria provided, single submitter | clinical testing | Variant summary: PALB2 c.3307G>A (p.Val1103Met) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) 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 0.00013 in 302930 control chromosomes, predominantly at a frequency of 0.00027 within the East Asian subpopulation in the gnomAD database. Due to the underrepresentation of East Asian subpopulation in the gnomAD database, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In addition, this variant was also found at a frequency of 0.0006 in 4.7K Japanese individuals in jMorp database (healthy Japanese volunteers; PMID: 29069501). c.3307G>A has been reported in the literature in sequencing studies reporting individuals affected with Hereditary Breast And Ovarian Cancer ( example, Casadei_2011, Gonzalez-Garay_2013, Thompson_2015, Kim_2017, Momozawa_2018), individuals undergoing multigene panel testing for Lynch syndrome (example, Thompson_2015), extra hepatic bile duct cancer (example, Terashima_2019), in male and female control cohorts of unaffected Japanese individuals (example, Momozawa_2018) and recently classified as benign in a study evaluating population-based screening for hereditary colorectal cancer variants in Japan (Fujita_2020). These reports do not provide unequivocal conclusions about association of the variant with PALB2 associated Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Wiltshire_2019). These results showed no damaging effect of this variant on homology directed repair (HDR) activity of PALB2. The following publications have been ascertained in the context of this evaluation (PMID: 24082139, 25980754, 21285249, 26283626, 27783279, 30287823, 31666926, 31636395, 33309985). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4; VUS, n=8). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. |
Mendelics | RCV000114616 | SCV001139982 | uncertain significance | Familial cancer of breast | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Cancer Genomics Group, |
RCV001030643 | SCV001193673 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research | |
Sema4, |
RCV000116103 | SCV002531166 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-01 | criteria provided, single submitter | curation | |
Center for Genomic Medicine, |
RCV000212827 | SCV004027060 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Leiden Open Variation Database | RCV000114616 | SCV001193392 | uncertain significance | Familial cancer of breast | 2019-05-13 | no assertion criteria provided | curation | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa. |
Genetic Services Laboratory, |
RCV000212827 | SCV003839806 | uncertain significance | not specified | 2022-06-27 | no assertion criteria provided | clinical testing | DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3307G>A, in exon 12 that results in an amino acid change, p.Val1103Met. This sequence change has been previously described in individuals with breast and other cancers as well as in a control population (PMID: 21285249, 27783279, 3028782 , 26283626, 33309985). Experimental studies showed no damaging effect of this variant on homology directed repair (HDR) activity of PALB2 (PMID: 31636395). This sequence change has been described in the gnomAD database with a global population frequency of 0.005% (dbSNP rs201657283). The p.Val1103Met change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1103Met substitution. Due to insufficient evidences the clinical significance of the p.Val1103Met change remains unknown at this time. |