Total submissions: 19
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000590540 | SCV000149974 | uncertain significance | not provided | 2023-06-22 | criteria provided, single submitter | clinical testing | Published functional studies are inconclusive: partial reduction of ChAM-mediated chromatin association, homology directed repair activity comparable to wild-type, reduced interaction with nucleosome core particles (Bleuyard et al., 2017; Boonen et al., 2019; Belotserkovskaya et al., 2020; Wiltshire et al., 2020); Observed in several individuals with PALB2-related and other cancers, but also in healthy controls (Rahman et al., 2007; Tischkowitz et al., 2012; Ramus et al., 2015; Tung et al., 2015; Yurgelun et al., 2015; Decker et al., 2017; Dominguez-Valentin et al., 2018; Dorling et al., 2021; Fonfria et al., 2021); Reported in a multiethnic exome array study, but no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 26315354, 22241545, 17200668, 26283626, 29458332, 28779002, 27930734, 25186627, 29387807, 31636395, 32255556, 32041954, 31757951, 35264596, 34357101, 26467025, 22193777, 26976419, 33471991, 34204722, 23555315) |
Ambry Genetics | RCV000116065 | SCV000186632 | likely benign | Hereditary cancer-predisposing syndrome | 2021-05-20 | 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 | RCV000114466 | SCV000218549 | likely benign | Familial cancer of breast | 2024-01-30 | criteria provided, single submitter | clinical testing | |
Cancer Genetics Laboratory, |
RCV000114466 | SCV000267998 | uncertain significance | Familial cancer of breast | 2015-06-01 | criteria provided, single submitter | case-control | |
Counsyl | RCV000114466 | SCV000489329 | uncertain significance | Familial cancer of breast | 2016-09-19 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000116065 | SCV000537539 | likely benign | Hereditary cancer-predisposing syndrome | 2022-05-10 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001255214 | SCV000699527 | likely benign | not specified | 2023-03-14 | criteria provided, single submitter | clinical testing | Variant summary: PALB2 c.1250C>A (p.Ser417Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 256854 control chromosomes, predominantly at a frequency of 0.00023 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1250C>A has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with breast cancer, colorectal cancer, and pancreatic ductal adenocarcinoma (example, Tischkowitz_2012, Yurgelun_2015, Cremin_2020, Fonfria_2021). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported (PMS2 c.2095G>C, p.D699H), providing supporting evidence for a benign role. In homology directed repair (HDR) assays, the variant was found to have either slightly reduced or normal activity (example, Boonen_2019, Wiltshire_2019). Fifteen other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=12) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. |
Prevention |
RCV000590540 | SCV000807071 | uncertain significance | not provided | 2018-01-04 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV000116065 | SCV000839041 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000590540 | SCV001134533 | benign | not provided | 2022-07-11 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV000590540 | SCV002010983 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV001255214 | SCV002067217 | uncertain significance | not specified | 2018-06-18 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000116065 | SCV002530596 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-22 | criteria provided, single submitter | curation | |
Genetics and Molecular Pathology, |
RCV000114466 | SCV002556675 | uncertain significance | Familial cancer of breast | 2022-01-12 | criteria provided, single submitter | clinical testing | |
Institute for Biomarker Research, |
RCV000116065 | SCV002819244 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-15 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000114466 | SCV004019723 | benign | Familial cancer of breast | 2023-04-03 | criteria provided, single submitter | clinical testing | This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. |
Center for Genomic Medicine, |
RCV001255214 | SCV004027086 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV003483472 | SCV004228275 | likely benign | Hereditary breast ovarian cancer syndrome | 2023-12-19 | criteria provided, single submitter | curation | Missense variant with relative high AF (0.000205773) in NFE. According to the ClinGen ACMG PALB2 v1.0.0 criteria we chose these criteria: BP1 (supporting benign): Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2., BS1 (strong benign): popmax:NFE popmax AF:0.000205773 |
Leiden Open Variation Database | RCV000590540 | SCV001193082 | uncertain significance | not provided | 2019-05-13 | no assertion criteria provided | curation | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. |