ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.394G>A (p.Val132Ile)

gnomAD frequency: 0.00015  dbSNP: rs142498771
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328227 SCV004035113 likely benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-03 reviewed by expert panel curation The NM_004360.5(CDH1):c.394G>A (p.Val132Ile) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023)
Ambry Genetics RCV000131738 SCV000186779 likely benign Hereditary cancer-predisposing syndrome 2019-02-12 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 RCV000204503 SCV000260293 benign Hereditary diffuse gastric adenocarcinoma 2024-01-30 criteria provided, single submitter clinical testing
GeneDx RCV000221311 SCV000278909 likely benign not provided 2020-04-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or colorectal cancer (Tung 2015, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 25186627)
Counsyl RCV000204503 SCV000489716 uncertain significance Hereditary diffuse gastric adenocarcinoma 2016-11-11 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003891670 SCV000806670 uncertain significance CDH1-related disorder 2023-12-14 criteria provided, single submitter clinical testing The CDH1 c.394G>A variant is predicted to result in the amino acid substitution p.Val132Ile. This variant was identified in an individual with breast cancer (Supplementary data, Tung et al. 2015. PubMed ID: 25186627), as well as in an individual with colorectal cancer (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68842333-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142546/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health RCV000131738 SCV000903071 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221311 SCV001134090 likely benign not provided 2022-11-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194008 SCV001363232 benign not specified 2020-06-16 criteria provided, single submitter clinical testing Variant summary: CDH1 c.394G>A (p.Val132Ile) 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. The variant allele was found at a frequency of 5.3e-05 in 282708 control chromosomes, predominantly at a frequency of 0.00048 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 23 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.394G>A has been reported in the literature in sequencing studies of individuals affected with breast cancer and colorectal cancer (example, Tung_2015, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 (benign, n=1; likely benign, n=3; VUS, n=3) with an emerging consensus towards a benign outcome since its previous evaluation. Based on the evidence outlined above, the variant was re-classified as benign.
Sema4, Sema4 RCV000131738 SCV002529182 likely benign Hereditary cancer-predisposing syndrome 2021-05-31 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000204503 SCV004019602 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.

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