rs587783050

chr16-68812263-G-Achr16-68812263-G-Cchr16-68812263-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.1137G>A(p.Thr379=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T379T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 2.78

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: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-68812263-G-A is Pathogenic according to our data. Variant chr16-68812263-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 156499.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68812263-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1137G>A	p.Thr379=	splice_region_variant, synonymous_variant	8/16	ENST00000261769.10
CDH1	NM_001317184.2	c.1137G>A	p.Thr379=	splice_region_variant, synonymous_variant	8/15
CDH1	NM_001317185.2	c.-479G>A		splice_region_variant, 5_prime_UTR_variant	8/16
CDH1	NM_001317186.2	c.-683G>A		splice_region_variant, 5_prime_UTR_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1137G>A	p.Thr379=	splice_region_variant, synonymous_variant	8/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 16, 2023	Criteria applied: PVS1,PS4,PS1_SUP,PM2_SUP, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change affects codon 379 of the CDH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH1 protein. RNA analysis indicates that this variant 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 variant has been observed in individuals with clinical features of hereditary diffuse gastric cancer (PMID: 15831593, 17221870, 17545690, 19725995, 21681551, 23709761, 26025002, 27682646; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156499). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in aberrant splicing, leading to expression of several defective alternate splicing products and high levels of allelic expression imbalance of the CDH1 gene and introduces a premature termination codon (PMID: 15831593, 18427545, 19965908). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 06, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data,17726045, 15831593]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [17545690, 17221870, 21681551]. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 11, 2021	Variant summary: CDH1 c.1137G>A (p.Thr379Thr) alters a conserved nucleotide located as the last nucleotide of exon 8 adjacent to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in a complex aberant pattern of alternatively spliced transcripts (example, Frebourg_2006). The variant was absent in 251452 control chromosomes. c.1137G>A has been reported in the literature in multiple individuals from families affected with Hereditary Diffuse Gastric Cancer (example, Frebourg_2006, Kaurah_2007, More_2007, Niemeyer_2020). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and one expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=6 to include the expert panel)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 08-12-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 19, 2016	- -
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	PVS1_Moderate; PS3; PS4; PM2 (PMID: 30311375) -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	Variant at the last nucleotide of an exon predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Frebourg et al., 2006; Karam et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26025002, 19965908, 17221870, 19725995, 21681551, 15831593, 21271559, 28117042, 27682646, 28281021, 22225527, 20373070, 19269290, 29468433, 17545690, 23709761, 26182300, 30311375, 32362280, 30426508, 34949788, 30745422, 31514334, 27995193, 18427545) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CDH1: PS4, PM2, PVS1:Moderate, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 25, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	This variant causes a G>A nucleotide substitution at the last nucleotide of exon 8 of the CDH1 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies using patient-derived cells have shown that this variant causes a complex aberrant splicing affecting exon 8 (PMID: 15831593, 18427545, 19965908). This variant has been reported in multiple individuals affected with diffuse gastric cancer (PMID: 15831593, 17221870, 17545690, 21271559, 21681551, 23709761, 27682646, 32362280) and lobular breast cancer (PMID: 30426508). 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 2022	The c.1137G>A mutation (also known as p.T379T) is located in coding exon 8 of the CDH1 gene. This mutation results from a G to A substitution at nucleotide position 1137. This alteration occurs in the last nucleotide of coding exon 8, adjacent to the canonical splice donor site, and leads to the generation of an alternately spliced transcript harboring a premature stop codon (Karam R et al. Oncogene. 2008 Jul;27:4255-60; Ambry internal data). This mutation has been observed in multiple HDGC families (Lynch HT et al. Fam Cancer. 2011 Dec;10:667-72; More H et al. Hum. Mutat. 2007 Feb;28:203; Kaurah P et al. JAMA. 2007 Jun;297:2360-72; Pantelis D et al. Int J Colorectal Dis. 2016 Dec;31:1825-1833), including one family where this mutation segregated with disease through two generations and was also found in three family members with both gastric cancer and cleft lip and palate, and another family member with gastric cancer and cleft lip (Frebourg T et al. J. Med. Genet. 2006 Feb;43:138-42). It was also seen in a patient with invasive ductal triple negative breast cancer and in her aunt with bilateral lobular breast cancer (Schubert S et al. Int. J. Cancer. 2019 Jun;144(11):2683-2694). Based on the available evidence to date, this alteration is classified as a pathogenic mutation. -

Gastric cancer, familial diffuse, and cleft lip with or without cleft palate Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2006

- -

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.1137G>A p.(Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 15831593). Additionally, this variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 15831593, 17545690, 17221870, 21681551, 27995193). 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): PVS1_Moderate, PM2_Supporting, PS3, PS4. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 09, 2022

PS4_STR, PS3, PM2_SUP, PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	22
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.33		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783050; hg19: chr16-68846166; COSMIC: COSV55733400; COSMIC: COSV55733400;