chr16-68737419-G-A

Variant names:

• chr16-68737419-G-A
• rs786201212
• NM_004360.5:c.4G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The CDH1 c.4G>A (p.Gly2Ser) missense variant has a frequency of 0.00002 (2 of 128,626) in gnomAD, with a maximum allele frequency of 0.00008 (2 of 24,378) in the Latino subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; unpublished). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA187442/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:2
• Conservation: PhyloP100: 2.03
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.4G>A	p.Gly2Ser	missense	Exon 1 of 16	NP_004351.1
	CDH1	NM_001317184.2		c.4G>A	p.Gly2Ser	missense	Exon 1 of 15	NP_001304113.1
	CDH1	NM_001317185.2		c.-1612G>A		5_prime_UTR	Exon 1 of 16	NP_001304114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.4G>A	p.Gly2Ser	missense	Exon 1 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.4G>A	p.Gly2Ser	missense	Exon 1 of 15	ENSP00000414946.2
	CDH1	ENST00000566612.5	TSL:1	n.4G>A		non_coding_transcript_exon	Exon 1 of 15	ENSP00000454782.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000155 AC: 2 AN: 128626 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000820

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 AF: 0.00000217 AC: 3 AN: 1381422 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 681938

African (AFR) AF: 0.0000320 AC: 1 AN: 31236

American (AMR) AF: 0.0000559 AC: 2 AN: 35760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25102

East Asian (EAS) AF: 0.00 AC: 0 AN: 35678

South Asian (SAS) AF: 0.00 AC: 0 AN: 78968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078528

Other (OTH) AF: 0.00 AC: 0 AN: 57680

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	1	-	Hereditary diffuse gastric adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.048
Sift	Benign	0.043	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.19	B
Vest4		0.43
MutPred		0.36		Gain of phosphorylation at G2 (P = 0.0267)
MVP		0.81
MPC		0.89
ClinPred		0.79	D
GERP RS		1.9
PromoterAI		-0.080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.098
gMVP		0.54

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

Other links and lift over

dbSNP: rs786201212; hg19: chr16-68771322;