NM_004360.5:c.79C>T

Variant names:

• chr16-68738327-C-T
• rs878854696
• NM_004360.5:c.79C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.79C>T (p.Pro27Ser) variant has allele frequency <1 out of 100, 000 in the gnomAD cohort (1/156646 in gnomAD v2.1.1; PM2_Supporting). No additional evidence met criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10583401/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:9 B:1
• Conservation: PhyloP100: 1.41
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: 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.79C>T	p.Pro27Ser	missense	Exon 2 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.79C>T	p.Pro27Ser	missense	Exon 2 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.-1537C>T		5_prime_UTR	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.79C>T	p.Pro27Ser	missense	Exon 2 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.79C>T	p.Pro27Ser	missense	Exon 2 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000566612.5	TSL:1	n.79C>T		non_coding_transcript_exon	Exon 2 of 15	ENSP00000454782.1	H3BNC6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000638 AC: 1 AN: 156646 AF XY: 0.0000121

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: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1395484 Hom.: 0 Cov.: 31 AF XY: 0.00000436 AC XY: 3 AN XY: 688240

African (AFR) AF: 0.00 AC: 0 AN: 31486

American (AMR) AF: 0.00 AC: 0 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 35572

South Asian (SAS) AF: 0.00 AC: 0 AN: 78572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1076956

Other (OTH) AF: 0.00 AC: 0 AN: 57812

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.098
Sift	Benign	0.27	T
Sift4G	Benign	0.73	T
Polyphen		0.044	B
Vest4		0.32
MutPred		0.55		Loss of catalytic residue at P27 (P = 1e-04)
MVP		0.71
MPC		0.27
ClinPred		0.090	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.092
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs878854696; hg19: chr16-68772230;