Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000227820 | SCV004812905 | benign | Hereditary diffuse gastric adenocarcinoma | 2024-03-25 | reviewed by expert panel | curation | The c.2336G>A (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 779 (p.Arg779Gln). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; internal clinical data). This variant has been observed in more than 10 (134) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC. (BS2; PMID: 29522266, 36436516; ClinVar SCVs: SCV000172951.7, SCV000288462.10, SCV000210875.16; internal lab contributors). In summary, this variant meets the criteria to be classified as benign for hereditary diffuse gastric cancer based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 variant curation expert panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_S. |
Ambry Genetics | RCV000129040 | SCV000172951 | likely benign | Hereditary cancer-predisposing syndrome | 2020-08-20 | 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. |
Gene |
RCV000212385 | SCV000210875 | uncertain significance | not provided | 2023-06-05 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and/or family history of breast cancer (Hauke et al., 2018; Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 27499925, 28522829, 26643872, 22850631, 15235021, 36436516, 29522266) |
Labcorp Genetics |
RCV000227820 | SCV000288462 | likely benign | Hereditary diffuse gastric adenocarcinoma | 2024-01-20 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000227820 | SCV000488643 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2016-05-12 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000129040 | SCV000684425 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-17 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glutamine at codon 779 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals with breast cancer (PMID: 29522266, Lovejoy et al. 2018). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=5.305 (95%CI 0.639 to 44.07); p-value=0.13; Leiden Open Variation Database DB-ID CDH1_000359) (PMID: 33471991). This variant has been identified in 5/282808 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, |
RCV001375527 | SCV001572384 | uncertain significance | not specified | 2023-02-03 | criteria provided, single submitter | clinical testing | Variant summary: CDH1 c.2336G>A (p.Arg779Gln) results in a conservative amino acid change located in the cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251462 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2336G>A has been reported in the literature in one individual affected with breast cancer (Hauke_2018). This report does not provide unequivocal conclusions about association of the variant with breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
European Reference Network on Genetic Tumour Risk Syndromes |
RCV000227820 | SCV003926929 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2022-08-01 | criteria provided, single submitter | clinical testing | BS2_Supporting (PMID: 30311375) |
Myriad Genetics, |
RCV000227820 | SCV004019596 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-03-06 | 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. |
Baylor Genetics | RCV003460883 | SCV004215598 | uncertain significance | Familial cancer of breast | 2023-10-30 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV003965073 | SCV004791917 | uncertain significance | CDH1-related disorder | 2024-05-23 | no assertion criteria provided | clinical testing | The CDH1 c.2336G>A variant is predicted to result in the amino acid substitution p.Arg779Gln. This variant has been reported in multiple individuals with a personal or familial history of breast cancer (Table S2, Hauke et al. 2018. PubMed ID: 29522266; Table S5, Garcia-Pelaez et al. 2022. PubMed ID: 36436516). This variant has interpretations ranging from benign to uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140840/). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |