rs1060501244

Positions:

• chr16-68828204-G-A
• chr16-68828204-G-C
• chr16-68828204-G-T

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PS3 PS4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.2195G>A variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID:17545690 15235021). This variant has also been reported in at least 12 families with HDGC criteria (PS4; PMID:17545690 15235021 and laboratory internal data). 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 (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS3, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16615410/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 3.10

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 9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2195G>A	p.Arg732Gln	missense_variant	14/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2012G>A	p.Arg671Gln	missense_variant	13/15
CDH1	NM_001317185.2	c.647G>A	p.Arg216Gln	missense_variant	14/16
CDH1	NM_001317186.2	c.230G>A	p.Arg77Gln	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2195G>A	p.Arg732Gln	missense_variant	14/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461736 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 732 of the CDH1 protein (p.Arg732Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with diffuse gastric cancer and lobular breast cancer (PMID: 15235021, 17545690, 18442100, 26072394, 29589180). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406663). 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 have shown that this missense change affects CDH1 function (PMID: 15235021). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	PS3; PS4; PM2; PP3 (PMID: 30311375) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 15, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15235021, 17545690, 18442100, 22020549, 26072394]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 17545690]. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 22, 2022	This missense variant replaces arginine with glutamine at codon 732 of the CDH1 protein. Splice site prediction tools suggest that this variant may create a new splice acceptor site. An RNA study has reported aberrant splicing utilizing this new splice site, resulting in the deletion of 32 nucleotides from exon 14 and a premature translation stop signal (PMID: 17545690). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals with hereditary diffuse gastric cancer (DGC) and/or lobular breast cancer (LBC) in the literature (PMID: 15235021, 17545690, 17634464, 18442100, 19269290, 22020549, 23073328, 26072394, 26182300, 29589180, 35070997). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2022	The p.R732Q pathogenic mutation (also known as c.2195G>A) is located in coding exon 14 of the CDH1 gene. This alteration results from a G to A substitution at nucleotide position 2195. The arginine at codon 732 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple HDGC patients and families (Brooks-Wilson et al. J Med Genet. 2004 Jul;41 (7):508-17; Kaurah et al. JAMA. 2007 Jun 6;297(21):2360-72; Fujita et al. Am J Surg Pathol. 2012 Nov;36(11):1709-17; Chung DC et al. N Engl J Med 2007 Jul 19; 357(3):283-91; Hakkaart C et al. Fam. Cancer. 2019 01;18(1):83-90). In addition, RT-PCR analysis showed that the p.R732Q alteration resulted in complex splicing and deletion of 32 base pairs at the start of exon 14 by activating a cryptic acceptor site (Kaurah P et al. JAMA. 2007 Jun;297(21):2360-72). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 29, 2021	PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CDH1: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -

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

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Nov 27, 2023

The c.2195G>A variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690 15235021). This variant has also been reported in at least 12 families with HDGC criteria (PS4; PMID: 17545690 15235021 and laboratory internal data). 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 (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS3, PS4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.46
MutPred		0.81		Gain of catalytic residue at R732 (P = 0.0928);.;.;
MVP		0.88
MPC		0.95
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2
DS_AL_spliceai		0.42		Position offset: -30

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501244; hg19: chr16-68862107; COSMIC: COSV55728376; COSMIC: COSV55728376;