The c.808T>G (p.Ser270Ala) variant has a maximum subpopulation frequency of 0.002269 (0.2269%, 57 of 25124 alleles) in the European (Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1). This variant has also has been observed in more than 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; SCV000185687.6, SCV000254832.8). In summary, this variant meets criteria to be classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BS2.

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26182300, 11948460, 19725995, 17545690, 11705864, 22098830, 27582386, 29928469, 30333958, 32426482)

Variant summary: CDH1 c.808T>G (p.Ser270Ala) results in a conservative amino acid change located in the second cadherin repeat (IPR002126) of 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 0.00044 in 282828 control chromosomes, predominantly at a frequency of 0.0023 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 80 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.808T>G has been reported in the literature in individuals affected with gastric cancer and breast/ovary cancer (e.g. Ikonen 2001, Brovkina 2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At least one publication reported experimental evidence evaluating an impact on protein function, demonstarating that the variant resulted in a strong adhesion but a bit lower than that of WT, the effect on cell migration in a wound closure assay was similar to WT, however, the variant protein was not activatable in CHO cells (Petrova 2016). The significance of these results at the cellular level remains however unclear. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4 classifying it as likely benign, and 1 as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.

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.

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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.

Converted during submission from untested to not provided.