ClinVar

Description

The CDH1 p.Ala102Thr variant was identified in 1 of 282 proband chromosomes (frequency: 0.004) from individuals or families with breast or ovarian cancer (Mannan 2016). The variant was also identified in dbSNP (ID: rs368492235) as "With Uncertain significance", and in ClinVar (classified as likely benign by Invitae, GeneDx and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by Ambry Genetics and Counsyl). The variant was identified in control databases in 60 of 246028 chromosomes (1 homozygous) at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15302 chromosomes (freq: 0.00007), European in 1 of 111500 chromosomes (freq: 0.000009), and South Asian in 58 of 30780 chromosomes (freq: 0.002); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Ala102 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.