rs780375749

Variant names:

• chr16-68801666-G-A
• rs780375749
• NM_004360.5:c.164-4G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68801666-G-A
• chr16-68801666-G-C
• chr16-68801666-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM2_Supporting BS2 BP4

This summary comes from the ClinGen Evidence Repository: The c.164-4G>A (NM_004360.5) variant in CDH1 occurs in the splice donor region of intron 2. This variant has been observed in more than 10 individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; Ambry, GeneDx, Invitae). This variant occurs in one in 251,376 alleles in gnomAD 2.1.1 (less than one out of 100,000), within the European Non-Finnish population (one in 113,662 alleles) PM2_Supporting. In silico splice site predictors suggest that this variant does not impact splicing (BP4). However, splicing has not been assessed by in vitro assays. In summary, this variant meets the criteria to be classified as likely benign for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2, BP4. (CDH1 VCEP specifications version 3.1; 04/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA192317/MONDO:0100488/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001260
• Clinical Significance: Likely benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.305

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 Likely_benign. Variant got -4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.164-4G>A		splice_region_variant, intron_variant	Intron 2 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.164-4G>A		splice_region_variant, intron_variant	Intron 2 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1452-4G>A		splice_region_variant, intron_variant	Intron 2 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1656-4G>A		splice_region_variant, intron_variant	Intron 2 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.164-4G>A		splice_region_variant, intron_variant	Intron 2 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251376 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458060 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725622

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:2

Sep 12, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 05, 2018

GeneDx

Significance: Likely 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. -

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

Aug 02, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.164-4G>A (NM_004360.5) variant in CDH1 occurs in the splice donor region of intron 2. This variant has been observed in more than 10 individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; Ambry, GeneDx, Invitae). This variant occurs in one in 251,376 alleles in gnomAD 2.1.1 (less than one out of 100,000), within the European Non-Finnish population (one in 113,662 alleles) PM2_Supporting. In silico splice site predictors suggest that this variant does not impact splicing (BP4). However, splicing has not been assessed by in vitro assays. In summary, this variant meets the criteria to be classified as likely benign for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2, BP4. (CDH1 VCEP specifications version 3.1; 04/24/2023) -

Hereditary cancer-predisposing syndrome Benign:1

Sep 19, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0020
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: rs780375749; hg19: chr16-68835569;