ClinVar Genomic variation as it relates to human health

The c.604G>A (p.Val202Ile) variant has an allele frequency of 0.00354 (0.35%, 109/30,772 alleles) in the South Asian subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1.

Variant summary: The CDH1 variant, c.604G>A (p.Val202Ile) causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a "benign"outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 72/121206 (1/1683 including 1 homozygote), predominantly in the South Asian cohort, 64/16478 (1/257 including 1 homozygote), which exceeds the estimated maximum expected allele frequency for a pathogenic CDH1 variant of 1/35335. Therefore, suggesting that the variant is a common polymorphism found in population(s) of South Asian origins. The variant of interest has been reported in affected individuals via publication(s) including a publication indicating a MLH1 variant is causal for the phenotype, not the variant of interest. Multiple reputable clinical laboratories have cited the variant with conflicting classifications, "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence, therefore the variant of interest is classified as Benign.

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 variant is associated with the following publications: (PMID: 23431106, 24728327, 28135048, 26182300, 21696387)

This alteration is classified as 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.

The CDH1 p.Val202Ile variant was identified in the literature in 1 of 472 proband chromosomes (frequency: 0.002) from individuals or families with gastric cancer and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Chen 2013, Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs546716073) as "With Uncertain significance, other allele" and ClinVar (classified as likely benign by Ambry Genetics, GeneDx, and Illumina Clinical Services Laboratory; and as benign by Invitae). The variant was not identified in Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 126 of 276950 chromosomes (1 homozygous) at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: South Asian in 109 of 30772 chromosomes (freq: 0.004), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34408 chromosomes (freq: 0.00003), and East Asian in 15 of 18866 chromosomes (freq: 0.0008), while the variant was not observed in the African, European, Ashkenazi Jewish, or Finnish populations. The variant was observed in a patient with gastric cancer as co-occurring with a pathogenic variant in MLH1 (Chen 2013) and was identified by our laboratory in an individual that also carried a pathogenic variant in PMS2, increasing the likelihood that this is a benign variant. The p.Val202 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, HumanSpliceFinder) do not predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.