rs1440280370

Variant names:

• chr16-68737464-G-A
• rs1440280370
• NM_004360.5:c.48+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68737464-G-A
• chr16-68737464-G-C
• chr16-68737464-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_Moderate PM5_Supporting PM2_Supporting PS4_Moderate PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.48+1G>A is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID:20719348, 24366306). The variant was also found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; SCV000617359.1). 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_Strong, PM2_Supporting, PS4_Moderate and PP1_Moderate, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396451431/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 NM_004360.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.52
• Publications: 4 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.48+1G>A		splice_donor_variant, intron_variant	Intron 1 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.48+1G>A		splice_donor_variant, intron_variant	Intron 1 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1568+1G>A		splice_donor_variant, intron_variant	Intron 1 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1772+1G>A		splice_donor_variant, intron_variant	Intron 1 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.48+1G>A		splice_donor_variant, intron_variant	Intron 1 of 15	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.48+1G>A		splice_donor_variant, intron_variant	Intron 1 of 14	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.48+1G>A		splice_donor_variant, intron_variant	Intron 1 of 14	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.48+1G>A		splice_donor_variant, intron_variant	Intron 1 of 14	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 130556 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1385264 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 684244

African (AFR) AF: 0.00 AC: 0 AN: 31462

American (AMR) AF: 0.00 AC: 0 AN: 36386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 35922

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080444

Other (OTH) AF: 0.00 AC: 0 AN: 57856

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20719348, 38873722, 30745422]. -

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong; PS4_Moderate; PM2; PP1_Moderate (PMID: 30311375) -

not provided Pathogenic:1

Jul 20, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted CDH1 c.48+1G>A or IVS1+1G>A and consists of a G>A nucleotide substitutionat the +1 position of intron 1 of the CDH1 gene. This variant destroys a canonical splice donor site and is predicted tocause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNAdecay or to an abnormal protein product. CDH1 c.48+1G>A has been reported in at least two families; one presentingwith multiple cases of diffuse gastric cancer while the other is reported to only have lobular breast cancer (Pandalai2011, Petridis 2014). Based on the current evidence, we consider this variant to be pathogenic -

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

Aug 29, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.48+1G>A is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 20719348, 24366306). The variant was also found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; SCV000617359.1). 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_Strong, PM2_Supporting, PS4_Moderate and PP1_Moderate, PM5_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.48+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the CDH1 gene. This alteration has been reported in a family affected with gastric cancers, colon cancer, and signet cell carcinoma of the cecum. Three unaffected members of this family were found to carry the c.48+1G>A pathogenic mutation and elected prophylactic gastrectomies. Post-surgical evaluations of all three gastrectomy specimens showed multiple foci of intramucosal adenocarcinoma and/or of signet ring cell carcinoma in situ (Pandalai PK et al. Surgery. 2011 Mar;149(3):347-55; Fujita H et al. Am J Surg Pathol. 2012 Nov;36(11):1709-17). This mutation has also been reported in one individual with a family history of breast cancer and a personal history of bilateral lobular breast cancer in situ (LCIS) and bilateral invasive lobular breast cancer (ILC) diagnosed at age 51 (Petridis C et al. Br J Cancer. 2014 Feb 18;110(4):1053-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.60	D
PhyloP100		4.5
GERP RS		4.1
PromoterAI		-0.45	Neutral
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -1

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

Other links and lift over

dbSNP: rs1440280370; hg19: chr16-68771367;