rs139757930

Positions:

• chr16-68833284-C-G
• chr16-68833284-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004360.5(CDH1):​c.2440-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,682 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: CDH1 NM_004360.5 splice_region, intron
• Scores: Splicing: ADA: 0.0005419
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: -0.395

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]

CDH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-68833284-C-G is Benign according to our data. Variant chr16-68833284-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 127926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68833284-C-G is described in Lovd as [Likely_benign]. Variant chr16-68833284-C-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0015 (229/152284) while in subpopulation AMR AF= 0.00255 (39/15294). AF 95% confidence interval is 0.00192. There are 1 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2440-6C>G		splice_region_variant, intron_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2257-6C>G		splice_region_variant, intron_variant			NP_001304113.1
CDH1	NM_001317185.2	c.892-6C>G		splice_region_variant, intron_variant			NP_001304114.1
CDH1	NM_001317186.2	c.475-6C>G		splice_region_variant, intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2440-6C>G		splice_region_variant, intron_variant		1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00180 AC: 453 AN: 251368 Hom.: 2 AF XY: 0.00175 AC XY: 238 AN XY: 135898

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00133 AC: 1940 AN: 1461398 Hom.: 4 Cov.: 32 AF XY: 0.00137 AC XY: 997 AN XY: 727024

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.00608

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74452

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00192 Hom.: 0

Bravo AF: 0.00160

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:28

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CDH1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2016	Variant summary: Variant affects a non-conserved intronic nucleotide located at a position not widely known to affect splicing. Mutation taster predicts the variant to be neutral along with 5/5 in silico tools via Alamut predicting no significant effect on normal splicing by the variant. The variant was in the large and broad cohorts of the ExAC project at an allele frequency of o,1% which is 63 times higher than the maximal expected allele frequency of a disease causing CDH1 allele (0.0028%) indicating a neutral impact. The variant showed lack of co-segregation with HDGC in one family (Grodecka_GCC_2014) and was shown not to affect splicing and the expression level of the protein (Grodecka_GCC_2014; Molinaro_GCC_2014) further supporting a benign nature. Additionally, clinical diagnostic centers classify variant as Likely Benign/Benign (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary diffuse gastric adenocarcinoma Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, 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	BS1; BS2; BS3; BP4 (PMID: 30311375) -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 24, 2024	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 04, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 14, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 15, 2017	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 24, 2019

- -

Malignant tumor of prostate Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CDH1 c.2440-6C>G variant was identified in 3 of 462 proband chromosomes (frequency: 0.006) from individuals or families with diffuse gastric and lung cancer (Guilford 2007, More 2007, Yorczyk 2015). The variant was also identified in the following databases: dbSNP (ID: rs139757930) as With Likely benign, ClinVar (classified as benign by Invitae, as likely benign by GeneDx and Ambry Genetics), Clinvitae (classified as likely benign by ClinVar, Invitae), Insight Colon Cancer Gene Variant Database (1X), and the Zhejiang Colon Cancer Database. The variant was identified in control databases in 453 (1 homozygous) of 277200 chromosomes at a frequency of 0.0016 in the following populations: European in 215 of 126702 chromosomes (freq. 0.002), Latino in 126 of 34420 chromosomes (freq. 0.004), Ashkenazi Jewish in 73 of 10152 chromosomes (freq. 0.007), Other in 29 of 6466 chromosomes (freq. 0.004), South Asian in 6 of 30782 chromosomes (freq.0.0002), African in 4 of 24024 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The c.2440-6C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. There is conflicting evidence in the literature regarding effect on splicing. The variant causes abnormal RNA transcripts compared to RNA from a healthy unrelated control Individuals in More et al. (2007), while in Grodeck√° (2014) results showed mostly correctly spliced transcripts of both wild type and c.2440-6C>G variants. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.0
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00054
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139757930; hg19: chr16-68867187; COSMIC: COSV55739563;