Submissions for variant NM_004360.5(CDH1):c.446T>C (p.Leu149Pro)

dbSNP: rs780955025

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166436	SCV000217231	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-21	criteria provided, single submitter	clinical testing	The p.L149P variant (also known as c.446T>C), located in coding exon 4 of the CDH1 gene, results from a T to C substitution at nucleotide position 446. The leucine at codon 149 is replaced by proline, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000410957	SCV000488803	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-06-20	criteria provided, single submitter	clinical testing
Invitae	RCV000410957	SCV000637829	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 149 of the CDH1 protein (p.Leu149Pro). This variant is present in population databases (rs780955025, 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: 186787). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000166436	SCV001734014	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 149 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 hereditary cancer in the literature. This variant has been identified in 1/251404 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.
GeneDx	RCV001574163	SCV001800928	uncertain significance	not provided	2021-11-29	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
Myriad Genetics, Inc.	RCV000410957	SCV004019539	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-03	criteria provided, single submitter	clinical testing	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.