Submissions for variant NM_004360.5(CDH1):c.164T>G (p.Val55Gly)

gnomAD frequency: 0.00008  dbSNP: rs587778174

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328184	SCV001943346	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000321508.8, SCV000153979.11). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Invitae	RCV000119234	SCV000153979	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131233	SCV000186188	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	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.
GeneDx	RCV000656817	SCV000321508	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Color Diagnostics, LLC DBA Color Health	RCV000131233	SCV000684372	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 55 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 reported for this variant. This variant has been reported in an individuals affected with breast cancer and colorectal cancer, but also in unaffected individuals (PMID: 24969172, 28135145, 28944238, 24728327, 33471991; [FLOSSIES database](https://whi.color.com/variant/16-68835573-T-G)). This variant has been identified in 7/282786 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	RCV000119234	SCV000785172	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120511	SCV000919114	likely benign	not specified	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.164T>G (p.Val55Gly) results in a non-conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence, and impacts the first nucleotide of exon 3. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. Lack of impact on splicing was confirmed by RNA sequencing studies (Karam_2019). The variant allele was found at a frequency of 2.4e-05 in 251390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.164T>G, has been reported in the literature in individuals affected with colon cancer, breast cancer cases and controls and recurrent pregnancy loss (Yurgelun_2017, DeRycke_2017, Quintero-Ronderos_2017, Dorling_2021) . These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. Eight clinical diagnostic laboratories including one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters have classified as VUS while 3 submitters including an expert panel have classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656817	SCV001134062	uncertain significance	not provided	2020-01-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120511	SCV002069928	uncertain significance	not specified	2019-12-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131233	SCV002529082	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120511	SCV002760848	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000119234	SCV003926998	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000119234	SCV004019606	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.
PreventionGenetics, part of Exact Sciences	RCV003390803	SCV004120322	uncertain significance	CDH1-related disorder	2023-04-07	criteria provided, single submitter	clinical testing	The CDH1 c.164T>G variant is predicted to result in the amino acid substitution p.Val55Gly. This variant has been reported in an individual with colorectal cancer that harbored a pathogenic MUTYH variant (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). It has been reported in an individual with breast cancer that harbored variants in other genes (Table S2, Wen et al. 2014. PubMed ID: 24969172). It has been reported in an individual with recurrent pregnancy loss (Tables 1 and 2, Quintero-Ronderos et al. 2017. PubMed ID: 29016666). It has been reported in an individual from a healthy, ancestry diverse cohort (Table S1, Bodian et al. PubMed ID: 24728327). The results of RT-PCR analysis suggest this variant does not impact splicing (eTable, Karam et al. 2019. PubMed ID: 31642931). It has also been reported as a somatically-acquired alteration in a pleomorphic xanthoastrocytoma (Table 1, Chan et al. 2017. PubMed ID: 28699883). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68835573-T-G). It has conflicting interpretation for likely benign and uncertain significance in ClinVar. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492514	SCV004240422	uncertain significance	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
ITMI	RCV000120511	SCV000084664	not provided	not specified	2013-09-19	no assertion provided	reference population