Submissions for variant NM_004360.5(CDH1):c.371G>A (p.Arg124His)

gnomAD frequency: 0.00002  dbSNP: rs115418995

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328210	SCV004035090	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.371G>A (p.Arg124His) missense variant has a frequency of 0.02010% in Africans (5/24870 alleles) in the gnomAD v2.1.1 cohort. This variant has been observed in at least 10 (31) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000637819.6, SCV000184938.6). In summary, the clinical significance of this variant is classified as of likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Ambry Genetics	RCV000130108	SCV000184938	likely benign	Hereditary cancer-predisposing syndrome	2019-02-16	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.
GeneDx	RCV000732060	SCV000210897	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28873162, 15235021, 36436516, 24493355, 36243179)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000732060	SCV000600986	uncertain significance	not provided	2020-12-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535278	SCV000637819	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-31	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 124 of the CDH1 protein (p.Arg124His). This variant is present in population databases (rs115418995, gnomAD 0.02%). This missense change has been observed in individual(s) with CDH1-related conditions (PMID: 24493355, 28873162, 36436516). ClinVar contains an entry for this variant (Variation ID: 141538). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Counsyl	RCV000535278	SCV000786040	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-02-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000535278	SCV000839076	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000732060	SCV000859944	uncertain significance	not provided	2018-03-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130108	SCV000911836	likely benign	Hereditary cancer-predisposing syndrome	2017-06-14	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153420	SCV003843530	benign	Ovarian cancer	2022-01-01	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	RCV000535278	SCV003927026	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PS4_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000535278	SCV004020013	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	RCV003415950	SCV004118081	uncertain significance	CDH1-related disorder	2023-05-09	criteria provided, single submitter	clinical testing	The CDH1 c.371G>A variant is predicted to result in the amino acid substitution p.Arg124His. This variant was reported in an individual with diffuse gastric cancer (Molinaro et al. 2014. PubMed ID: 24493355). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68835780-G-A), and is listed in ClinVar with confliciting interpretations of uncertain, likely benign and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/141538/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355829	SCV001550829	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Arg124His variant was identified in 1 of 64 proband chromosomes (frequency: 0.016) from individuals or families with diffuse gastric cancer (Molinaro 2014). The variant was also identified in dbSNP (ID: rs115418995) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and classified as uncertain significance by GeneDx, Invitae, Counsyl, and one other clinical laboratory), and in Zhejiang University Database (1x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 6 of 276422 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24004 chromosomes (freq: 0.0002), European in 1 of 126036 chromosomes (freq: 0.000008), and East Asian in 1 of 18866 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Arg124 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, single-nucleotide primer extension and RT-PCR assays did not detect allelic imbalance or aberrant splicing (Molinaro 2014). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.