Submissions for variant NM_004360.5(CDH1):c.512T>G (p.Phe171Cys)

dbSNP: rs772622109

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328367	SCV001365463	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-21	reviewed by expert panel	curation	The c.512T>G (p.Phe171Cys) variant has an allele frequency: 1:251320 (<one out 100.000 alleles) in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). It has been observed in 4 probands w/o DGS, SRC tumor or LBC and whose families do not suggest HDGC (BS2_Supporting; SCV000572669.4, SCV000637836.3). In summary, this variant meets criteria to be classified as VUS based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2_Supporting.
GeneDx	RCV000480184	SCV000572669	uncertain significance	not provided	2020-03-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529730	SCV000637836	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 171 of the CDH1 protein (p.Phe171Cys). This variant is present in population databases (rs772622109, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423041). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000579712	SCV000684466	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 171 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 1/251320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000579712	SCV002646918	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-10	criteria provided, single submitter	clinical testing	The p.F171C variant (also known as c.512T>G), located in coding exon 4 of the CDH1 gene, results from a T to G substitution at nucleotide position 512. The phenylalanine at codon 171 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.