Submissions for variant NM_004360.5(CDH1):c.2371C>T (p.Leu791Phe)

gnomAD frequency: 0.00002  dbSNP: rs786202598

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165485	SCV000216216	likely benign	Hereditary cancer-predisposing syndrome	2021-11-15	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	RCV000205557	SCV000261099	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 791 of the CDH1 protein (p.Leu791Phe). This variant is present in population databases (rs786202598, gnomAD 0.0009%). This missense change has been observed in individual(s) with rectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 185969). 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. 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.
Counsyl	RCV000205557	SCV000487913	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2015-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165485	SCV000906604	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 791 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with rectal cancer (PMID: 27978560) in the literature. This variant has been identified in 1/251468 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.
Fulgent Genetics, Fulgent Genetics	RCV002492661	SCV002800916	uncertain significance	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2021-10-19	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000205557	SCV003926931	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2; BS2_Supporting (PMID: 30311375)
GeneDx	RCV001355113	SCV003927551	uncertain significance	not provided	2023-05-24	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 an individual with mismatch repair-proficient rectal cancer (Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 22850631, 32019277, 15235021, 27978560)
Myriad Genetics, Inc.	RCV000205557	SCV004019531	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	RCV003462174	SCV004215612	uncertain significance	Familial cancer of breast	2024-01-14	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355113	SCV001549901	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CDH1 p.Leu791Phe variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang University Database. The variant was identified in dbSNP (ID: rs786202598) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, Invitae, and Counsyl), and Clinvitae (2x as in ClinVar). The variant was identified in control databases in 1 of 246242 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 111698 chromosomes (freq: 0.000009); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu791Phe residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant amino acid Phenylalanine (Phe) is present in green spotted pufferfish, increasing the likelihood that this variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.