Submissions for variant NM_004360.5(CDH1):c.2131C>G (p.Leu711Val)

gnomAD frequency: 0.00002  dbSNP: rs121964871

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328147	SCV001142276	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-18	reviewed by expert panel	curation	The c.2131C>G variant is <1/50,000 alleles (0.002%, 2/128,916 alleles) in the non-Finnish European subpopulation (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). Use of the Bayesian point system for this variant with conflicting evidence. Therefore, the clinical significance of this variant is likely benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2.
Ambry Genetics	RCV000130551	SCV000185421	likely benign	Hereditary cancer-predisposing syndrome	2021-02-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000196099	SCV000254818	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-11-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000382368	SCV000329234	uncertain significance	not provided	2018-06-21	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.2131C>G at the cDNA level, p.Leu711Val (L711V) at the protein level, and results in the change of a Leucine to a Valine (CTG>GTG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been published as a somatic variant in an endometrial carcinoma with no evidence of tumoral loss of heterozygosity (Risinger 1994). CDH1 Leu711Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Transmembrane domain (Brooks-Wilson 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Leu711Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130551	SCV000689498	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 711 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. A gastric cancer case-control study reported this variant in 41/359 cases and 25/368 controls (PMID: 28352678). This variant has been observed in over ten individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not meet hereditary diffuse gastric cancer syndrome (ClinVar: SCV001142276.2; Color internal data). This variant has been identified in 2/281652 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	RCV000196099	SCV000785302	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-07-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818150	SCV002069004	uncertain significance	not specified	2018-04-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000196099	SCV004020065	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-07	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000382368	SCV004227599	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	BP6, PM2_supporting
OMIM	RCV000013017	SCV000033262	pathogenic	Endometrial carcinoma	1994-05-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356883	SCV001552163	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Leu711Val variant was identified in the heterozygous or homozygous state in 41 of 359 Chinese probands with gastric cancer and in 25 of 368 healthy individuals, although the allele frequencies could not be calculated for either population as the frequencies of heterozygotes and homozygotes were not provided separately (Lin 2014). This variant has also been reported somatically in an endometrial carcinoma with no evidence of loss of heterozygosity in tumour tissue (Risinger 1994). The variant was identified in dbSNP (ID: rs121964871) as “With Pathogenic allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color and Counsyl). The variant was identified in control databases in 2 of 276082 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 126488 chromosomes (freq: 0.000016), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu711 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 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.