Submissions for variant NM_004360.5(CDH1):c.1679C>T (p.Thr560Met)

gnomAD frequency: 0.00002  dbSNP: rs746481984

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167921	SCV000218569	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 560 of the CDH1 protein (p.Thr560Met). This variant is present in population databases (rs746481984, gnomAD 0.004%). 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: 188085). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV000215364	SCV000276020	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	The p.T560M variant (also known as c.1679C>T), located in coding exon 11 of the CDH1 gene, results from a C to T substitution at nucleotide position 1679. The threonine at codon 560 is replaced by methionine, an amino acid with similar properties. In one study, this variant was detected with a carrier frequency of 0.0001 in 12490 male controls of Japanese ancestry and was not detected in 7051 unselected breast cancer patients, 53 male breast cancer patients or 11241 female controls in the same study (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration has also been identified in an East Asian patient with a sarcoma diagnosed at age 35 (Ballinger ML et al. Lancet Oncol, 2016 Sep;17:1261-71), and was reported in 1/701 Brazilian individuals with features consistent with a hereditary breast and/or ovarian cancer syndrome (Faria JP et al. Breast Cancer Res Treat, 2024 Jun). 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. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000485776	SCV000570318	uncertain significance	not provided	2023-08-22	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; Identified in unaffected individual(s) but not in any cases from a breast cancer study (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 36243179, 15235021, 22850631, 30287823)
Counsyl	RCV000167921	SCV000785038	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-03-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193300	SCV001362046	uncertain significance	not specified	2019-07-18	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1679C>T (p.Thr560Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance (Momozawa_2018 and gnomAD). To our knowledge, no occurrence of c.1679C>T in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four 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.
Color Diagnostics, LLC DBA Color Health	RCV000215364	SCV001735575	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-22	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 560 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 sarcoma (PMID: 27498913) and in an individual unaffected with cancer (PMID: 30287823). This variant has been identified in 1/251482 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.
Mendelics	RCV001193300	SCV002518040	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000167921	SCV004019561	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	RCV003462252	SCV004215642	uncertain significance	Familial cancer of breast	2023-09-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000167921	SCV004807247	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000485776	SCV005411344	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing	PM2_moderate