Submissions for variant NM_004360.5(CDH1):c.2629G>A (p.Gly877Arg)

gnomAD frequency: 0.00001  dbSNP: rs555842031

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480709	SCV000573531	uncertain significance	not provided	2022-02-04	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 an individual with breast cancer and in an individual with a personal and/or family history of diffuse gastric cancer (Momozawa 2018, Marwitz 2020); This variant is associated with the following publications: (PMID: 15235021, 22850631, 30287823, 33322525)
Ambry Genetics	RCV000567842	SCV000666292	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The p.G877R variant (also known as c.2629G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2629. The glycine at codon 877 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in an individual with gastric cancer (Marwitz T et al. Cancers (Basel), 2020 Dec;12:). This alteration was observed in 1 of 7,051 unselected female breast cancer patients and in 1 of 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 Oct 4;9(1):4083). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000567842	SCV000689522	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 877 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with gastric cancer in the literature (PMID: 33322525). This variant has been identified in 3/251452 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639205	SCV000760774	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 877 of the CDH1 protein (p.Gly877Arg). This variant is present in population databases (rs555842031, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer and/or clinical features of hereditary diffuse gastric cancer (PMID: 30287823, 33322525). ClinVar contains an entry for this variant (Variation ID: 423788). 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.
Sema4, Sema4	RCV000567842	SCV002529160	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	curation
Baylor Genetics	RCV003464035	SCV004215674	uncertain significance	Familial cancer of breast	2023-08-07	criteria provided, single submitter	clinical testing