Submissions for variant NM_004360.5(CDH1):c.488G>C (p.Cys163Ser)

dbSNP: rs748783182

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228101	SCV000288485	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 163 of the CDH1 protein (p.Cys163Ser). This variant is present in population databases (rs748783182, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 239907). 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.
GeneDx	RCV000484023	SCV000566522	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Singh et al., 2018); This variant is associated with the following publications: (PMID: 25275298, 29470806, 15235021, 22850631)
Ambry Genetics	RCV000574597	SCV000661623	likely benign	Hereditary cancer-predisposing syndrome	2022-03-16	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.
Color Diagnostics, LLC DBA Color Health	RCV000574597	SCV000689546	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 163 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 breast and/or ovarian cancer (PMID: 29470806). This variant has been identified in 23/251356 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.
Baylor Genetics	RCV004567742	SCV005060058	uncertain significance	Familial cancer of breast	2024-03-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000228101	SCV005407392	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-09-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.