rs587780537

chr16-68810224-G-Achr16-68810224-G-Cchr16-68810224-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004360.5(CDH1):c.715G>A(p.Gly239Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G239E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 6.30

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-68810224-G-A is Pathogenic according to our data. Variant chr16-68810224-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 132709.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68810224-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.715G>A	p.Gly239Arg	missense_variant	6/16	ENST00000261769.10
CDH1	NM_001317184.2	c.715G>A	p.Gly239Arg	missense_variant	6/15
CDH1	NM_001317185.2	c.-901G>A		5_prime_UTR_variant	6/16
CDH1	NM_001317186.2	c.-1105G>A		5_prime_UTR_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.715G>A	p.Gly239Arg	missense_variant	6/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2018	Variant summary: CDH1 c.715G>A (p.Gly239Arg) results in a non-conservative amino acid change located in the Cadherin domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict that the variant creates a 3' acceptor site without a significant impact on the canonical splicing site. One publication reports experimental evidence that this variant affects mRNA splicing, causing the deletion of the first 29 base pairs from exon 6 (validated by minigene analysis)(Kaurah_2007) (ACMG PP3 and ACMG PS3 consistent with ClinGen recommendations by Lee_CDH1_Human Mut_2018). The variant was absent in 246230 control chromosomes (gnomAD) (ACMG PM2). The variant, c.715G>A, has been reported in the literature in multiple individuals and families affected with Hereditary Diffuse Gastric Cancer, where it segregated with disease (Kaurah_CDH1_JAMA_2007, Shirts_2016, Mandelker_2017, Kim_2013) and in one Breast Cancer case (Susswein_2016). However, it was also found in a family in which a 79 yo individual carrying this variant was disease-free, suggesting reduced penetrance (More_2007). Overall, these data indicate that the variant is likely to be associated with disease (ACMG PS4 consistent with ClinGen recommendations by Lee_CDH1_Human Mut_2018). Functional studies showed that this variant is associated with deficient E-cadherin function with no significant/moderate changes in protein expression levels (More_2007, Kim_2013), increased motility with reduced affinity for EGFR and higher EGFR activation (Mateus_2009, Figueiredo_2010). However, one other study showed that this variant does not affect adhesion but affects transduction of signaling across the membrane (Petrova_2016). In accordance with the ClinGen recommendations, we did not use functional assays for missense variants as evidence for CDH1 variant classification. However, the variant still meets the ClinGen recommended ACMG PS3 criteria as it results in an abnormal out of frame transcript as discussed above. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS 1x, likely pathogenic/pathogenic 5x). Based on the evidence outlined above, the variant was classified as pathogenic and also consistent with the ClinGen recommended criteria for CDH1 variant classification (ACMG PS3, PS4, PM2, PP3). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [17221870, 17545690, 23264079, 26182300, Myriad internal data]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [17545690, Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 239 of the CDH1 protein (p.Gly239Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast and/or diffuse gastric cancer (PMID: 17221870, 17545690, 23264079, 26681312, 26845104, 28873162, 32269045; Invitae). ClinVar contains an entry for this variant (Variation ID: 132709). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 17221870, 17545690, 19268661, 27582386, 30311375). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 17545690, 33619332; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 19, 2022	The p.G239R pathogenic mutation (also known as c.715G>A), located in coding exon 6 of the CDH1 gene, results from a G to A substitution at nucleotide position 715. The glycine at codon 239 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with either a personal history of early onset diffuse gastric cancer and/or a family history consistent with hereditary diffuse gastric cancer syndrome (Kim S et al. Fam. Cancer. 2013 Sep;12:503-7; More H et al. Hum. Mutat. 2007 Feb;28:203; Suriano GJ et al. J. Mol. Med. 2006 Dec;84:1023-31; Ambry internal data); but has also been reported in unaffected individuals (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; More H et al. Hum. Mutat. 2007 Feb;28:203). Protein studies have shown that this alteration confers deficient E-cadherin function with respect to intercellular adhesion and suppression of invasion in vitro (More H et al. Hum. Mutat. 2007 Feb;28:203), motility (Mateus AR et al. Exp. Cell Res. 2009 May;315:1393-402), and adhesion activation from intracellular triggers (Petrova YI et al. Mol. Biol. Cell, 2016 Nov;27:3233-3244). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have detected an abnormal out of frame transcript with the first 29 base pairs of exon 6 deleted in individuals with this alteration (Kaurah P et al. JAMA. 2007 Jun;297:2360-72, Ambry internal data). Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 01, 2020	This missense variant replaces glycine with arginine at codon 239 in the extracellular domain of the CDH1 protein. A functional study has shown that this variant disrupts RNA splicing and causes a deletion of the first 29 bases of exon 6 in cells isolated from a carrier individual as well as in minigene assay (PMID: 17545690). This aberrant splicing is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with diffuse gastric cancer (PMID: 17221870, 17545690, 23264079, 26845104) and breast cancer (PMID: 26681312). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2021	Identified in patients with diffuse gastric cancer, but also in unaffected relatives (Kaurah 2007, More 2007, Kim 2013, Wang 2020); RNA studies demonstrate abnormal splicing, with an out-of-frame deletion of the first 29 base pairs of exon 6 being the most abundant transcript as well as a small amount of full-length transcript harboring the G293R missense change (Kaurah 2007, Yelskaya 2021); Published functional studies demonstrate a negative impact on E-cadherin function with respect to suppression of invasion, increased cell motility, increased EGFR activation, and intracellular signaling; however, there have been mixed results regarding its impact on intercellular adhesion (More 2007, Mateus 2009, Petrova 2016); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 23264079, 26681312, 16924464, 17221870, 20373070, 22098830, 26845104, 26182300, 28873162, 29577179, 31246251, 33809393, 15235021, 22850631, 34012620, 31511843, 32269045, 19268661, 27582386, 17545690, 33619332) -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Neoplasm of ovary;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 03, 2022

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 29, 2023

The c.715G>A (p.Gly239Arg) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 16 families (18) meeting HDGC clinical criteria (PS4_very strong; PMID: 17545690, 23264079, 23264079, 26182300; SCV000153869.9, SCV000273881.6, internal laboratory contributors). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). There are RNA assays demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690, 33619332). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (v3.1): PS4_very strong, PS3, PM2_supporting, PP3. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	36
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;T;T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.4	D;.;.;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;.;.;.;D
Sift4G	Uncertain	0.042	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.78
MutPred		0.88		Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);
MVP		0.86
MPC		1.0
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587780537; hg19: chr16-68844127; COSMIC: COSV55729844; COSMIC: COSV55729844;