Submissions for variant NM_004360.5(CDH1):c.387+1G>A

gnomAD frequency: 0.00001  dbSNP: rs587781919

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328213	SCV001142257	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-21	reviewed by expert panel	curation	The c.387+1G>A variant is a canonical splice variant predicted to result in small in-frame amino acid deletions/insertions (PVS1_Moderate). This variant has an allele frequency of 0.00002 in gnomAD (4/245268) and is present with a frequency of 0.00012 (4/33552) in the Latino subpopulation (http://gnomad.broadinstitute.org). RT-PCR analysis demonstrated that this variant results in two additional in-frame transcripts, including a longer transcript with intronic retention of 57 bp and a shorter transcript with a 159 bp deletion (PS3_Supporting; https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20]). This variant has also been reported in at least three individuals not meeting HDGC clinical criteria (BS2_Supporting; https://ascopubs.org/doi/full/10.1200/PO.16.00021, https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20], PMID: 26845104). In summary, this variant is classified as a variant of uncertain significance based on conflicting ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PS3_Supporting, BS2_Supporting.
Ambry Genetics	RCV000130267	SCV000185111	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The c.387+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the CDH1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in multiple in-frame splicing events of unknown functional significance (Ambry internal data). Another alteration at this same splice donor site, c.387+2T>A, is also predicted by in silico models to disrupt splicing. Internal RNA studies demonstrated that the c.387+2T>A variant similarly results in multiple in-frame splicing events of unknown functional significance (Ambry internal data). In addition, the c.387+1G>A alteration has been identified in individuals that do not have a personal or family history suggestive of hereditary diffuse gastric cancer (Ambry internal data). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130267	SCV000266059	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-21	criteria provided, single submitter	clinical testing	Functional analysis revealed insertion of a portion of intron 3 with deletion of a portion of exon 3, resulting in an in frame protein product which may or may not affect CDH1 protein function (PMID: 27880784). This variant has been identified in two unrelated individuals with breast cancer and one unaffected individual, all of whom have no personal or family history of gastric cancer (internal laboratory data). This variant is present in population databases (gnomAD 0.00159%) and its genomic position is well-conserved across species.
GeneDx	RCV000588476	SCV000573612	uncertain significance	not provided	2021-08-24	criteria provided, single submitter	clinical testing	Canonical splice site variant with an unclear effect on protein function; Splicing studies using patient cDNA/RNA demonstrate that this variant results in full-length transcript as well as smaller in-frame events that may not affect the mature E-Cadherin protein (Yelskaya 2016, Karam 2019); Observed in individuals tested at GeneDx and in published literature with personal or family history of breast cancer, but no gastric cancer (Yelskaya 2016); Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31642931, 30311375, 31246251, 28152038)
Invitae	RCV000528857	SCV000637824	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is present in population databases (rs587781919, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26845104, 36436516). ClinVar contains an entry for this variant (Variation ID: 141661). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (PMID: 31642931; Invitae; Poster G20 in http://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588476	SCV000698398	uncertain significance	not provided	2017-06-05	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.387+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict loss of canonical splicing donor site. ESEfinder predict loss of binding motif for SF2/ASF. However, these predictions have yet to be confirmed by peer-reviewed functional studies. One meeting abstract reported that cDNA analysis of an unaffected 41 year old woman carrying variant of interest indicated that c.387+1G>A variant resulted in two additional transcripts besides the normal transcript: a longer transcript and a shorter transcript are both in-frame alterations within the precursor peptide with no predicted disruption to the precursor protein cleavage site. Authors speculated both novel transcripts would result in a mature E-cadherin protein (Yelskaya_AMP_2016). This variant was found in 1/119850 control chromosomes in ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). However, the MAF in Latinos is 0.000088 (1/11424) in ExAC and 0.0001192 (4/33552) in gnomAD. This frequency is about 3-4 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant, suggesting this is possibly a benign polymorphism found primarily in the populations of Latino origin, although the allele numbers in both datasets are very small. This variant has been reported in another unaffected individual with BrC family history by a published report (Lowstuter_2017). In addition, two clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic and one classified it as VUS, all without evidence for independent evaluation. Taken together, considering lack of clinical and functional evidence, this variant is currently classified as variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV000130267	SCV001349954	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-31	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the +1 position of intron 3 of the CDH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. However, this variant has been reported to result in transcripts that are predicted to cause in-frame protein change in the prodomain of the CDH1 protein (PMID: 31642931; poster G20 in https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf). This variant has been reported in an individual affected with breast cancer (PMID: 26845104) and in healthy individuals (PMID: 31642931). This variant has been identified in 4/250346 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.
Sema4, Sema4	RCV000130267	SCV002529177	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-24	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000528857	SCV003927032	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1_Moderate, PS3_Supporting, BS2_Supporting (PMID: 30311375)
Baylor Genetics	RCV003460918	SCV004215676	uncertain significance	Familial cancer of breast	2023-08-05	criteria provided, single submitter	clinical testing