Submissions for variant NM_004360.5(CDH1):c.1988A>G (p.Tyr663Cys)

gnomAD frequency: 0.00005  dbSNP: rs372182377

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129549	SCV000184329	likely benign	Hereditary cancer-predisposing syndrome	2020-07-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000766709	SCV000210922	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, pancreatic and prostate cancer (PMID: 29368341, 28767289, 29522266); This variant is associated with the following publications: (PMID: 28767289, 29368341, 29522266, 15235021, 22850631)
Invitae	RCV000197868	SCV000254816	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212376	SCV000593918	uncertain significance	not specified	2016-07-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129549	SCV000684390	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 663 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer, prostate cancer and pancreatic cancer (PMID: 28767289, 29368341, 29522266). This variant has been identified in 5/282856 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212376	SCV002555849	uncertain significance	not specified	2022-06-13	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1988A>G (p.Tyr663Cys) results in a non-conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Five 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 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1988A>G has been reported in the literature in individuals affected with Pancreatic cancer or Prostate cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV000197868	SCV002579161	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-04-26	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000197868	SCV003843167	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-11-29	criteria provided, single submitter	clinical testing	The CDH1 c.1988A>G (p.Tyr663Cys) missense change has a maximum subpopulation frequency of 0.0040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766709	SCV004220812	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000031 (4/129178 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 29522266 (2018)), prostate cancer (PMID: 29522266 (2018)), and pancreatic cancer (PMID: 28767289 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355594	SCV001550521	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Tyr663Cys variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or Zhejiang University database. The variant was identified in dbSNP (ID: rs372182377) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and two other submitters). The variant was identified in 5 of 277208 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), European in 4 of 126710 chromosomes (freq: 0.00003), but not in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Tyr663 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.