rs781513008

Variant names:

• chr16-68810329-G-A
• rs781513008
• NM_004360.5:c.820G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68810329-G-A
• chr16-68810329-G-C
• chr16-68810329-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BP2_Strong BS1

This summary comes from the ClinGen Evidence Repository: The c.820G>A (p.Gly274Ser) variant has been observed in >10 (25) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000760786.3, SCV000216659.5 and SCV000520889.4). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer or lobular breast cancer (BP2_Strong; SCV000520889.4). The c.820G>A variant has an allele frequency of 0.001037 (0.1037%, 5/4822 alleles) in the South Asian subpopulation of the gnomAD v.3.1 cohort (BS1). In summary, the clinical significance of this variant is benign, ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong, BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA194486/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 3.03
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.820G>A	p.Gly274Ser	missense	Exon 6 of 16	NP_004351.1
	CDH1	NM_001317184.2		c.820G>A	p.Gly274Ser	missense	Exon 6 of 15	NP_001304113.1
	CDH1	NM_001317185.2		c.-796G>A		5_prime_UTR	Exon 6 of 16	NP_001304114.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.820G>A	p.Gly274Ser	missense	Exon 6 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.820G>A	p.Gly274Ser	missense	Exon 6 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.891G>A		non_coding_transcript_exon	Exon 5 of 15

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251432 AF XY: 0.000140

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 AF: 0.0000554 AC: 81 AN: 1461752 Hom.: 1 Cov.: 31 AF XY: 0.0000770 AC XY: 56 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000927 AC: 80 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Hereditary diffuse gastric adenocarcinoma (2)
-	1	1	not specified (2)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	-	1	Familial cancer of breast;C1140680:Ovarian cancer (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.055	N
PhyloP100		3.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.17
Sift	Benign	0.035	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.21
MutPred		0.43		Gain of phosphorylation at G274 (P = 0.0546)
MVP		0.79
MPC		0.62
ClinPred		0.23	T
GERP RS		3.3
Varity_R		0.32
gMVP		0.57
Mutation Taster		=84/16	polymorphism

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: rs781513008; hg19: chr16-68844232; COSMIC: COSV55729074;