Submissions for variant NM_004360.5(CDH1):c.1296C>G (p.Asn432Lys)

dbSNP: rs187862045

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003993849	SCV004812904	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-09-25	reviewed by expert panel	curation	NM_004360.5(CDH1):c.1296C>G (p.Asn432Lys) variant has been observed in more than 10 (29) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; ClinVar SCVs: SCV000217409.6, SCV000545471.7, internal lab contributors). The CDH1-VCEP recommended a variant to reach a likely benign classification based on BS2 alone. In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Ambry Genetics	RCV000166605	SCV000217409	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-19	criteria provided, single submitter	clinical testing	The p.N432K variant (also known as c.1296C>G), located in coding exon 9 of the CDH1 gene, results from a C to G substitution at nucleotide position 1296. The asparagine at codon 432 is replaced by lysine, an amino acid with similar properties. This variant has been reported in a diffuse gastric cancer patient; RNA analysis of gastric tissue obtained from this patient revealed that the this variant could generate a shortened transcript lacking exon 9, which was predicted to result in an in-frame deletion of 183 amino acids in the extracellular domain (Li X et al. Fam. Cancer 2013 Sep; 12(3):547-54). However, this transcript was not detected in the normal tissue from this individual (Li X et al. Fam. Cancer 2013 Sep; 12(3):547-54). In addition, internal RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). In a study of 99 Chinese breast cancer patients with family histories of cancer, this variant was observed in one patient with invasive ductal carcinoma diagnosed at age 47, who had a family history of two relatives with gastric cancer of unknown histology (Yang X et al. PLoS ONE 2015; 10(4):e0125571). This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This amino acid position is highly 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.
Invitae	RCV000460665	SCV000545471	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166605	SCV000903557	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 432 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and gastric cancer in the literature (PMID: 23435907, 25927356), but also in unaffected controls (PMID: 30287823). This variant has been identified in 6/251484 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193905	SCV001363073	uncertain significance	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1296C>G (p.Asn432Lys) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, one experimental study showed this variant generated the exon9-skipping (Li_2013). However, in the absence of experimental evidence evaluating an impact on protein function, this observation does not allow convincing conclusions about the variant effect. Furthermore, the ACMG guidelines for CDH1 variants recommend a supporting (not strong or moderate) weight for evidence that would result in in-frame transcripts such as deletion of exon 9 in CDH1. The variant allele was found at a frequency of 2.9e-05 in 274816 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1296C>G has been reported in the literature in individuals affected with breast cancer and gastric cancer as well as in two health controls (Li_2013, Yang_2015, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153452	SCV003843761	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567307	SCV005060101	uncertain significance	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000677870	SCV000804031	likely pathogenic	Neoplasm of stomach	2017-12-08	no assertion criteria provided	clinical testing