ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2254G>A (p.Val752Ile)

gnomAD frequency: 0.00002  dbSNP: rs587781351
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129135 SCV000183853 likely benign Hereditary cancer-predisposing syndrome 2024-02-28 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000229329 SCV000288457 likely benign Hereditary diffuse gastric adenocarcinoma 2024-01-19 criteria provided, single submitter clinical testing
GeneDx RCV000479491 SCV000572025 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.2254G>A at the cDNA level, p.Val752Ile (V752I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Val752Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. CDH1 Val752Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the cytoplasmic domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CDH1 Val752Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000229329 SCV000785048 uncertain significance Hereditary diffuse gastric adenocarcinoma 2017-04-04 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129135 SCV000908760 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265613 SCV002548317 uncertain significance not specified 2022-05-30 criteria provided, single submitter clinical testing Variant summary: CDH1 c.2254G>A (p.Val752Ile) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251480 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2254G>A has been reported in the literature in an individual affected with Breast Cancer (Adedokun_2020). 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 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc. RCV000229329 SCV004019595 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 RCV003460889 SCV004215607 uncertain significance Familial cancer of breast 2024-02-16 criteria provided, single submitter clinical testing

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