Submissions for variant NM_004360.5(CDH1):c.369C>G (p.His123Gln)

gnomAD frequency: 0.00001  dbSNP: rs778954591

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166535	SCV000217336	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-20	criteria provided, single submitter	clinical testing	The p.H123Q variant (also known as c.369C>G), located in coding exon 3 of the CDH1 gene, results from a C to G substitution at nucleotide position 369. The histidine at codon 123 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with adrenocortical carcinoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant was also observed in individuals suspected for a hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879, Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639218	SCV000760788	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 123 of the CDH1 protein (p.His123Gln). This variant is present in population databases (rs778954591, 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: 186880). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000166535	SCV000908715	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 123 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250664 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.
GeneDx	RCV002516501	SCV003195081	uncertain significance	not provided	2023-05-11	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 breast cancer and adrenocortical carcinoma (Zhang et al., 2015; Bonache et al., 2018; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 15235021, 26580448, 32885271, 30306255)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354427	SCV001549041	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.His123Gln variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs778954591) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics). The variant was identified in control databases in 1 of 245586 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 1 of 111136 chromosomes (freq: 0.00001); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.His123 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.