Submissions for variant NM_004360.5(CDH1):c.1592A>G (p.Asn531Ser)

dbSNP: rs1596960354

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813115	SCV000953456	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2019-09-16	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CDH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 531 of the CDH1 protein (p.Asn531Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine.
Color Diagnostics, LLC DBA Color Health	RCV001184394	SCV001350358	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 531 of the CDH1 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	RCV001184394	SCV002706801	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	clinical testing	The p.N531S variant (also known as c.1592A>G), located in coding exon 11 of the CDH1 gene, results from an A to G substitution at nucleotide position 1592. The asparagine at codon 531 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702445	SCV005202205	uncertain significance	not specified	2024-07-01	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1592A>G (p.Asn531Ser) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1592A>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 656646). Based on the evidence outlined above, the variant was classified as uncertain significance.