chr16-68801894-G-A

Position:

chr16-68801894-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PVS1_ModerateBS2_SupportingPS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.387+1G>A variant is a canonical splice variant predicted to result in small in-frame amino acid deletions/insertions (PVS1_Moderate). This variant has an allele frequency of 0.00002 in gnomAD (4/245268) and is present with a frequency of 0.00012 (4/33552) in the Latino subpopulation (http://gnomad.broadinstitute.org). RT-PCR analysis demonstrated that this variant results in two additional in-frame transcripts, including a longer transcript with intronic retention of 57 bp and a shorter transcript with a 159 bp deletion (PS3_Supporting; https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20]). This variant has also been reported in at least three individuals not meeting HDGC clinical criteria (BS2_Supporting; https://ascopubs.org/doi/full/10.1200/PO.16.00021, https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20], PMID:26845104). In summary, this variant is classified as a variant of uncertain significance based on conflicting ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PS3_Supporting, BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA166072/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CDH1
NM_004360.5 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance reviewed by expert panel U:10

Conservation

PhyloP100: 5.28

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PVS1

PS3

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.387+1G>A	splice_donor_variant	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.387+1G>A	splice_donor_variant
CDH1	NM_001317185.2 linkuse as main transcript	c.-1229+1G>A	splice_donor_variant
CDH1	NM_001317186.2 linkuse as main transcript	c.-1433+1G>A	splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.387+1G>A		splice_donor_variant		1	NM_004360.5	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250346

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460282

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 18, 2024	The c.387+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the CDH1 gene. This variant has been reported in an individual with a personal history of breast cancer diagnosed in Spain (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). In addition to the clinical data presented in the literature, this variant has been detected in multiple individuals with no reported features of CDH1-related diffuse gastric and lobular breast cancer (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in multiple in-frame splicing events of unknown functional significance (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Jun 21, 2019	Functional analysis revealed insertion of a portion of intron 3 with deletion of a portion of exon 3, resulting in an in frame protein product which may or may not affect CDH1 protein function (PMID: 27880784). This variant has been identified in two unrelated individuals with breast cancer and one unaffected individual, all of whom have no personal or family history of gastric cancer (internal laboratory data). This variant is present in population databases (gnomAD 0.00159%) and its genomic position is well-conserved across species. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 31, 2019	This variant causes a G>A nucleotide substitution at the +1 position of intron 3 of the CDH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. However, this variant has been reported to result in transcripts that are predicted to cause in-frame protein change in the prodomain of the CDH1 protein (PMID: 31642931; poster G20 in https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf). This variant has been reported in an individual affected with breast cancer (PMID: 26845104) and in healthy individuals (PMID: 31642931). This variant has been identified in 4/250346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2017	Variant summary: The CDH1 c.387+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict loss of canonical splicing donor site. ESEfinder predict loss of binding motif for SF2/ASF. However, these predictions have yet to be confirmed by peer-reviewed functional studies. One meeting abstract reported that cDNA analysis of an unaffected 41 year old woman carrying variant of interest indicated that c.387+1G>A variant resulted in two additional transcripts besides the normal transcript: a longer transcript and a shorter transcript are both in-frame alterations within the precursor peptide with no predicted disruption to the precursor protein cleavage site. Authors speculated both novel transcripts would result in a mature E-cadherin protein (Yelskaya_AMP_2016). This variant was found in 1/119850 control chromosomes in ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). However, the MAF in Latinos is 0.000088 (1/11424) in ExAC and 0.0001192 (4/33552) in gnomAD. This frequency is about 3-4 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant, suggesting this is possibly a benign polymorphism found primarily in the populations of Latino origin, although the allele numbers in both datasets are very small. This variant has been reported in another unaffected individual with BrC family history by a published report (Lowstuter_2017). In addition, two clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic and one classified it as VUS, all without evidence for independent evaluation. Taken together, considering lack of clinical and functional evidence, this variant is currently classified as variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2021	Canonical splice site variant with an unclear effect on protein function; Splicing studies using patient cDNA/RNA demonstrate that this variant results in full-length transcript as well as smaller in-frame events that may not affect the mature E-Cadherin protein (Yelskaya 2016, Karam 2019); Observed in individuals tested at GeneDx and in published literature with personal or family history of breast cancer, but no gastric cancer (Yelskaya 2016); Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31642931, 30311375, 31246251, 28152038) -

Hereditary diffuse gastric adenocarcinoma

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change affects a donor splice site in intron 3 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant is present in population databases (rs587781919, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26845104, 36436516). ClinVar contains an entry for this variant (Variation ID: 141661). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (PMID: 31642931; Invitae; Poster G20 in http://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, 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	PVS1_Moderate, PS3_Supporting, BS2_Supporting (PMID: 30311375) -

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 21, 2023

The c.387+1G>A variant is a canonical splice variant predicted to result in small in-frame amino acid deletions/insertions (PVS1_Moderate). This variant has an allele frequency of 0.00002 in gnomAD (4/245268) and is present with a frequency of 0.00012 (4/33552) in the Latino subpopulation (http://gnomad.broadinstitute.org). RT-PCR analysis demonstrated that this variant results in two additional in-frame transcripts, including a longer transcript with intronic retention of 57 bp and a shorter transcript with a 159 bp deletion (PS3_Supporting; https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20]). This variant has also been reported in at least three individuals not meeting HDGC clinical criteria (BS2_Supporting; https://ascopubs.org/doi/full/10.1200/PO.16.00021, https://jmd.amjpathol.org/article/S1525-1578(16)30178-7/pdf [G20], PMID: 26845104). In summary, this variant is classified as a variant of uncertain significance based on conflicting ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PS3_Supporting, BS2_Supporting. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Benign

0.92

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.97

MutationTaster

Benign

1.0

D;D

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over