Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000586292 | SCV000149741 | uncertain significance | not provided | 2020-03-11 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colon cancer (Raskin 2017); This variant is associated with the following publications: (PMID: 12414534, 12532420, 29212164) |
Ambry Genetics | RCV000115832 | SCV000185512 | likely benign | Hereditary cancer-predisposing syndrome | 2020-09-11 | 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. |
Invitae | RCV000229894 | SCV000288411 | likely benign | Hereditary diffuse gastric adenocarcinoma | 2024-01-30 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000229894 | SCV000488287 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2016-02-12 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000115832 | SCV000684319 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-05 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glutamine at codon 335 of the CDH1 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with gastric cancer (PMID: 12414534, 12532420), breast cancer (PMID: 32959997), and an individual affected with colorectal cancer (PMID: 29212164). This variant has been identified in 7/282636 chromosomes 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000855585 | SCV000698351 | uncertain significance | not specified | 2023-09-29 | criteria provided, single submitter | clinical testing | Variant summary: CDH1 c.1004G>A (p.Arg335Gln) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of 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 2.5e-05 in 395984 control chromosomes (gnomAD). The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (2.1e-05), suggesting that the variant may be benign. c.1004G>A has been reported in the literature in individuals affected with breast cancer (e.g., Momozawa_2018, Uyisenga_2020) and at least one individual with ovarian cancer (e.g., Villy_2021) and one with colorectal cancer (e.g., Raskin_2017). These reports do not provide unequivocal conclusions about association of the variant with breast cancer. Co-occurrences with pathogenic variants have been observed in our lab (RAD51C c.706-2A>G and PMS2 c.2186_2187delTC, p.Leu729GlnfsX6), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12532420, 12414534, 29212164, 30287823, 32959997, 34541275). Nine submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 8, likely benign, n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
Mendelics | RCV000229894 | SCV000839085 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2018-07-02 | criteria provided, single submitter | clinical testing | |
European Reference Network on Genetic Tumour Risk Syndromes |
RCV000229894 | SCV003926714 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2022-08-01 | criteria provided, single submitter | clinical testing | BS2_Supporting (PMID: 30311375) |
Myriad Genetics, |
RCV000229894 | SCV004020033 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-03-07 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
Center for Genomic Medicine, |
RCV000855585 | SCV004026641 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000586292 | SCV004220771 | uncertain significance | not provided | 2022-09-17 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.000085 (3/35426 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant was identified in a diffuse gastric cancer tissue (PMID: 12414534 (2002)) as well as in individuals affected with colorectal cancer (PMID: 29212164 (2017)) and breast cancer (PMID: 30287823 (2018), 32959997 (2020), 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |