rs876660223

Positions:

• chr16-68801803-G-A
• chr16-68801803-G-C
• chr16-68801803-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. BP7 BS2_Supporting PM2_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The c.297G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Leu99=) that is not predicted by SpliceAI, SSF, MaxEnt to impact splicing (BP4, BP7). In addition, it occurs at a nucleotide that is not conserved as shown by phastCons and (BP7). This variant has been observed in more than 3 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2_Supporting, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580080/MONDO:0100488/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH1 ENST00000261769.10 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:4
• Conservation: PhyloP100: -2.83

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 -2 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.
• BP7: 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/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.297G>A	p.Leu99=	synonymous_variant	3/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.297G>A	p.Leu99=	synonymous_variant	3/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1319G>A		5_prime_UTR_variant	3/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1523G>A		5_prime_UTR_variant	3/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.297G>A	p.Leu99=	synonymous_variant	3/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 11, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 12, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

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

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 02, 2023

The c.297G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Leu99=) that is not predicted by SpliceAI, SSF, MaxEnt to impact splicing (BP4, BP7). In addition, it occurs at a nucleotide that is not conserved as shown by phastCons and (BP7). This variant has been observed in more than 3 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2_Supporting, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2015

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	-0.87
CADD	Benign	0.026
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs876660223; hg19: chr16-68835706; COSMIC: COSV55732569;