Submissions for variant NM_004360.5(CDH1):c.394G>A (p.Val132Ile)

gnomAD frequency: 0.00015  dbSNP: rs142498771

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328227	SCV004035113	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The NM_004360.5(CDH1):c.394G>A (p.Val132Ile) 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). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023)
Ambry Genetics	RCV000131738	SCV000186779	likely benign	Hereditary cancer-predisposing syndrome	2019-02-12	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	RCV000204503	SCV000260293	benign	Hereditary diffuse gastric adenocarcinoma	2024-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000221311	SCV000278909	likely benign	not provided	2020-04-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or colorectal cancer (Tung 2015, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28135145, 25186627)
Counsyl	RCV000204503	SCV000489716	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-11-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131738	SCV000903071	likely benign	Hereditary cancer-predisposing syndrome	2016-04-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000221311	SCV001134090	likely benign	not provided	2022-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194008	SCV001363232	benign	not specified	2020-06-16	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.394G>A (p.Val132Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 282708 control chromosomes, predominantly at a frequency of 0.00048 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.394G>A has been reported in the literature in sequencing studies of individuals affected with breast cancer and colorectal cancer (example, Tung_2015, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=3; VUS, n=3) with an emerging consensus towards a benign outcome since its previous evaluation. Based on the evidence outlined above, the variant was re-classified as benign.
Sema4, Sema4	RCV000131738	SCV002529182	likely benign	Hereditary cancer-predisposing syndrome	2021-05-31	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000204503	SCV004019602	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	RCV003891670	SCV000806670	uncertain significance	CDH1-related disorder	2024-05-14	no assertion criteria provided	clinical testing	The CDH1 c.394G>A variant is predicted to result in the amino acid substitution p.Val132Ile. This variant has been identified in an individual with breast cancer (Supplementary data, Tung et al. 2015. PubMed ID: 25186627), as well as in an individual with colorectal cancer (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142546/). 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.