rs139757930

Variant names:

• chr16-68833284-C-G
• rs139757930
• NM_004360.5:c.2440-6C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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:29
• Conservation: PhyloP100: -0.395
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 127926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 229 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2440-6C>G		splice_region_variant, intron_variant	Intron 15 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2257-6C>G		splice_region_variant, intron_variant	Intron 14 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.892-6C>G		splice_region_variant, intron_variant	Intron 15 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.475-6C>G		splice_region_variant, intron_variant	Intron 14 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2440-6C>G		splice_region_variant, intron_variant	Intron 15 of 15	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

GnomAD2 exomes AF: 0.00180 AC: 453 AN: 251368 AF XY: 0.00175

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 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

African (AFR) AF: 0.000149 AC: 5 AN: 33462

American (AMR) AF: 0.00398 AC: 178 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 159 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5764

European-Non Finnish (NFE) AF: 0.00127 AC: 1407 AN: 1111580

Other (OTH) AF: 0.00189 AC: 114 AN: 60376

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

African (AFR) AF: 0.000361 AC: 15 AN: 41570

American (AMR) AF: 0.00255 AC: 39 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

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:29

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Mar 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH1: BP4, BS2 -

not specified Benign:7

Nov 22, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2020

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2019

King Laboratory, University of Washington

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary diffuse gastric adenocarcinoma Benign:6

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1; BS2; BS3; BP4 (PMID: 30311375) -

Hereditary cancer-predisposing syndrome Benign:5

Nov 04, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 14, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2017

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 27, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

May 24, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Prostate cancer Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00054
dbscSNV1_RF	Benign	0.052
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs139757930; hg19: chr16-68867187;