The c.2512A>G (p.Ser838Gly) 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 (Variant Interpretation Guidelines Version 3.1): BS2.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

In-silico analyses, including protein predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging; This variant is associated with the following publications: (PMID: 25801821, 29929997, 30374176, 8075649, 22470475, 25980754, 19139070, 10671552, 26674224, 27616075, 28993866, 9823469, 28767289, 31159747)

The CDH1 variant designated as NM_004360.3:c.2512A>G (p.Ser838Gly) is classified as likely benign in the context of hereditary diffuse gastric cancer syndrome (Hansford 2015, PMID:26182300). This variant was identified or imputed in several family members age 65 or older who have not had gastric cancer or lobular breast cancer. This variant is listed in population databases (rs121964872) and is found in approximately 1 out of 9000 individuals of European ancestry (http://gnomad.broadinstitute.org/). This variant is predicted to be tolerated by in silico prediction tools (SIFT, PolyPhen-2, Align-GVGD). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to cause hereditary diffuse gastric cancer syndrome. A smaller increase in cancer risk that the risk reported in the literature due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

BS2 (PMID: 30311375)

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.

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.

Variant summary: CDH1 c.2512A>G (p.Ser838Gly) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 273974 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.66 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), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, this frequency does not exceed the allele frequency threshold of 0.001 set by the ClinGen CDH1 variant curation expert panel (Lee_2018). c.2512A>G has been reported in the literature in individuals affected with cancer, including breast cancer, Lynch syndrome-associated cancer and pancreatic neuroendocrine tumor (Hauke_2018, Shindo_2017, Tung_2015, Yurgelun_2015, Schubert_2019). In one study, the variant was detected in an unaffected female proband (45 years old) from a BRCA1-positive (c.1016dupA, p.Val340fsX6) family with a history of breast and ovarian cancer (Stuebs_2018). In another study, 5 individuals older than 55 were reported in one family who had the variant but did not have gastric cancer, and only one had breast cancer (Tsai_2019). Another co-occurrence with a pathogenic variant has been reported in our internal database (BRCA2 c.6025C>T, p.Gln2009X), providing supporting evidence for a benign role. Furthermore, the variant of interest was detected in 2 women in the FLOSSIES database older than age 70 years who have never had cancer, providing further supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 8075649, 25980754, 25186627, 25882375, 27616075, 27930734, 28767289, 30089731, 30311375, 29522266, 30287823, 30374176, 30426508, 31159747, 28993866, 33980423, 35089076). ClinVar contains an entry for this variant (Variation ID: 12233). Based on the evidence outlined above, the variant was classified as likely benign.

CDH1: BP4, BS2

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.