16-68738409-G-A

Variant names:

• chr16-68738409-G-A
• rs876658680
• NM_004360.5:c.161G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.161G>A (p.Arg54Lys) missense variant is absent in the gnomAD 2.1.1 cohort (PM2_supporting; 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without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000274257.4, SCV000637737.4, unpublished data). In summary, although a conflicting code PM2_supporting is met, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting, BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580076/MONDO:0100488/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense, splice_region
• Scores: Splicing: ADA: 0.0003592
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:1
• Conservation: PhyloP100: 0.361
• Publications: 2 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: 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.161G>A	p.Arg54Lys	missense splice_region	Exon 2 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.161G>A	p.Arg54Lys	missense splice_region	Exon 2 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.-1455G>A		splice_region	Exon 2 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.161G>A	p.Arg54Lys	missense splice_region	Exon 2 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.161G>A	p.Arg54Lys	missense splice_region	Exon 2 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000566612.5	TSL:1	n.161G>A		splice_region non_coding_transcript_exon	Exon 2 of 15	ENSP00000454782.1	H3BNC6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 151972 AF XY: 0.00

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: 0.00000288 AC: 4 AN: 1391146 Hom.: 0 Cov.: 29 AF XY: 0.00000292 AC XY: 2 AN XY: 685650

African (AFR) AF: 0.00 AC: 0 AN: 31428

American (AMR) AF: 0.00 AC: 0 AN: 35434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25052

East Asian (EAS) AF: 0.00 AC: 0 AN: 35536

South Asian (SAS) AF: 0.00 AC: 0 AN: 78778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00000373 AC: 4 AN: 1072804

Other (OTH) AF: 0.00 AC: 0 AN: 57610

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	-	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	0.083
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.36
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.015	B
Vest4		0.31
MutPred		0.64		Gain of ubiquitination at R54 (P = 0.0325)
MVP		0.76
MPC		0.26
ClinPred		0.23	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.55
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.0020
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: rs876658680; hg19: chr16-68772312;