ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2201G>C (p.Arg734Thr)

gnomAD frequency: 0.00001  dbSNP: rs587781859
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000196295 SCV000254821 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 734 of the CDH1 protein (p.Arg734Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216593). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000480068 SCV000569108 uncertain significance not provided 2024-03-06 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Observed in 1/609 Brazilian control individuals aged 60 years or older, but was absent among 221 individuals with nonsyndromic orofacial clefting in a case-control study (PMID: 26123647); This variant is associated with the following publications: (PMID: 15235021, 22850631, 26123647)
Ambry Genetics RCV000561514 SCV000666271 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-13 criteria provided, single submitter clinical testing The p.R734T variant (also known as c.2201G>C), located in coding exon 14 of the CDH1 gene, results from a G to C substitution at nucleotide position 2201. The arginine at codon 734 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000561514 SCV000684406 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-23 criteria provided, single submitter clinical testing This missense variant replaces arginine with threonine at codon 734 of the CDH1 protein. Computational prediction tool 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251458 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.
Counsyl RCV000196295 SCV000784849 uncertain significance Hereditary diffuse gastric adenocarcinoma 2017-01-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001582696 SCV001821469 uncertain significance not specified 2021-08-08 criteria provided, single submitter clinical testing Variant summary: CDH1 c.2201G>C (p.Arg734Thr) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) 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 4e-06 in 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2201G>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have 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. RCV000196295 SCV004019556 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-03 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 RCV003462332 SCV004215597 uncertain significance Familial cancer of breast 2023-10-30 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000196295 SCV005402424 uncertain significance Hereditary diffuse gastric adenocarcinoma 2024-05-24 criteria provided, single submitter clinical testing The CDH1 c.2201G>C (p.Arg734Thr) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this change may affect splicing, but RNA studies are inconclusive (internal data). To our knowledge, this variant has not been reported in the literature in individuals with diffuse gastric and lobular breast cancer syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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