NM_004360.5(CDH1):c.1519T>A (p.Ser507Thr) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003229696.3

Allele description [Variation Report for NM_004360.5(CDH1):c.1519T>A (p.Ser507Thr)]

NM_004360.5(CDH1):c.1519T>A (p.Ser507Thr)

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.1519T>A (p.Ser507Thr)

HGVS:

NC_000016.10:g.68815713T>A
NG_008021.1:g.83422T>A
NM_001317184.2:c.1336T>A
NM_001317185.2:c.-30T>A
NM_001317186.2:c.-301T>A
NM_004360.5:c.1519T>AMANE SELECT
NP_001304113.1:p.Ser446Thr
NP_004351.1:p.Ser507Thr
NP_004351.1:p.Ser507Thr
LRG_301t1:c.1519T>A
LRG_301:g.83422T>A
LRG_301p1:p.Ser507Thr
NC_000016.9:g.68849616T>A
NM_004360.3:c.1519T>A
NM_004360.4:c.1519T>A

Protein change:

S446T

Molecular consequence:

NM_001317185.2:c.-30T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-301T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.1336T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.1519T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary diffuse gastric adenocarcinoma (HDGC)
Synonyms:: Hereditary diffuse gastric cancer
Identifiers:: MONDO: MONDO:0007648; MedGen: C1708349; Orphanet: 26106; OMIM: 137215

Recent activity

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AGENCOURT_13997046 NICHD_XGC_Tad1 Xenopus laevis cDNA clone IMAGE:6939697 5', mR...
AGENCOURT_13997046 NICHD_XGC_Tad1 Xenopus laevis cDNA clone IMAGE:6939697 5', mRNA sequence
gi|30751775|gnl|dbEST|17936223|gb|C 72.1|

Nucleotide
Chain Z, Capsid protein VP1
Chain Z, Capsid protein VP1
gi|1890518567|pdb|5IPI|Z

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003926809	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS	criteria provided, single submitter (Lee et al. (Hum Mutat. 2018))	Uncertain significance (Aug 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30311375, 36436516
SCV004665364	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003926809

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS

criteria provided, single submitter

(Lee et al. (Hum Mutat. 2018))

Uncertain significance
(Aug 1, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004665364

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 22, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants.

Lee K, Krempely K, Roberts ME, Anderson MJ, Carneiro F, Chao E, Dixon K, Figueiredo J, Ghosh R, Huntsman D, Kaurah P, Kesserwan C, Landrith T, Li S, Mensenkamp AR, Oliveira C, Pardo C, Pesaran T, Richardson M, Slavin TP, Spurdle AB, Trapp M, et al.

Hum Mutat. 2018 Nov;39(11):1553-1568. doi: 10.1002/humu.23650.

PubMed [citation]

PMID:: 30311375
PMCID:: PMC6188664

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

Garcia-Pelaez J, Barbosa-Matos R, Lobo S, Dias A, Garrido L, Castedo S, Sousa S, Pinheiro H, Sousa L, Monteiro R, Maqueda JJ, Fernandes S, Carneiro F, Pinto N, Lemos C, Pinto C, Teixeira MR, Aretz S, Bajalica-Lagercrantz S, Balmaña J, Blatnik A, Benusiglio PR, et al.

Lancet Oncol. 2023 Jan;24(1):91-106. doi: 10.1016/S1470-2045(22)00643-X. Epub 2022 Nov 24. Erratum in: Lancet Oncol. 2023 Jan;24(1):e10. doi: 10.1016/S1470-2045(22)00761-6.

PubMed [citation]

PMID:: 36436516
PMCID:: PMC9810541

See all PubMed Citations (3)

Details of each submission

From European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS, SCV003926809.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

"1 family not fulfilling 2020 HDGC criteria-Familial history of other cancers than gastric cancer or breast cancer"

PubMed [ID: 36436516]

Description

PM2 (PMID: 30311375)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	1	not provided

From Invitae, SCV004665364.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 507 of the CDH1 protein (p.Ser507Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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