Submissions for variant NM_004360.5(CDH1):c.2603G>A (p.Arg868His)

gnomAD frequency: 0.00001  dbSNP: rs369126891

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218816	SCV000273854	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	RCV000233357	SCV000288475	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 868 of the CDH1 protein (p.Arg868His). This variant is present in population databases (rs369126891, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of hereditary breast cancer and/or ovarian cancer (PMID: 32068069). ClinVar contains an entry for this variant (Variation ID: 230337). 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	RCV000485189	SCV000564842	uncertain significance	not provided	2024-01-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27149842, 30287823, 36243179)
Color Diagnostics, LLC DBA Color Health	RCV000218816	SCV000684444	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 868 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 30287823, 32068069, 33471991), as well as healthy control individuals (PMID: 3028782, 334719913). This variant has been identified in 4/251466 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.
Counsyl	RCV000233357	SCV000786111	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-02-26	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000485189	SCV002009852	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824693	SCV002074264	uncertain significance	not specified	2022-01-14	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2603G>A (p.Arg868His) results in a non-conservative amino acid change in 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 1.8e-05 in 273948 control chromosomes (gnomAD, Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2603G>A has been reported in the literature in individuals affected with Breast Cancer (example: Dorling_2021, Kwong_2020). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000233357	SCV004019540	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	RCV004567519	SCV005060082	uncertain significance	Familial cancer of breast	2024-02-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016577	SCV005644362	uncertain significance	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian cancer	2024-01-18	criteria provided, single submitter	clinical testing