rs1131690818

chr16-68819430-G-Achr16-68819430-G-Cchr16-68819430-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3 PP5_Strong

The NM_004360.5(CDH1):c.1711+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 1.36

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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 16-68819430-G-A is Pathogenic according to our data. Variant chr16-68819430-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 428630.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1711+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000261769.10
CDH1	NM_001317184.2	c.1528+5G>A		splice_donor_5th_base_variant, intron_variant
CDH1	NM_001317185.2	c.163+5G>A		splice_donor_5th_base_variant, intron_variant
CDH1	NM_001317186.2	c.-254-2571G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1711+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_004360.5	P1
	ENST00000563916.1	n.264-3771C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2021

This sequence change falls in intron 11 of the CDH1 gene. It does not directly 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with skipping of exon 11, which introduces a premature termination codon (PMID: 15235021). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with hereditary diffuse gastric cancer syndrome (PMID: 15235021, Invitae). ClinVar contains an entry for this variant (Variation ID: 428630). This variant is not present in population databases (ExAC no frequency). -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 21, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2017

The c.1711+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 11 in the CDH1 gene. This alteration, referred to as IVS11+5G>A, was reported in an individual diagnosed with diffuse gastric cancer at age 48 who had two family members with confirmed diffuse gastric cancer both at age 44 and five family members with breast cancer, one of which was confirmed as lobular. Additional RT-PCR analyses indicated that this alteration led to exon 11 skipping (Brooks-Wilson AR et al. J Med Genet. 2004 Jul;41(7):508-17). This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, c.1711+5G>A is classified as a pathogenic mutation. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

CDH1: PM2, PP1, PS3:Supporting -

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

Uncertain significance, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 03, 2023

The c.1711+5G>A variant in CDH1 is an intronic variant which switches a G to an A in the +5 position of intron 11. This variant is known in five families, three of which meet HDGC criteria (PS4_moderate; PMID: 15235021, AmbryGenetics, Invitae, Color and CeTaG internal data). This variant is completely absent from population databases such as gnomAD (PM2_supporting). There is evidence of abnormal RNA expression of this variant allele as a functional consequence of incorrect slicing, but further studies are required to confirm this evidence (PS3_supporting; PMID: 15235021). In summary, this variant is classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen CDH1 Variant Curation Expert Panel: PS3_supporting, PS4_moderate, PM2_supporting. (CDH1 VCEP specifications version 3.1; 06/26/2023) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	17
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.050		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: rs1131690818; hg19: chr16-68853333;