NM_004360.5(CDH1):c.1702A>G (p.Thr568Ala) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 15, 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:: RCV000473023.14

Allele description [Variation Report for NM_004360.5(CDH1):c.1702A>G (p.Thr568Ala)]

NM_004360.5(CDH1):c.1702A>G (p.Thr568Ala)

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.1702A>G (p.Thr568Ala)

HGVS:

NC_000016.10:g.68819416A>G
NG_008021.1:g.87125A>G
NM_001317184.2:c.1519A>G
NM_001317185.2:c.154A>G
NM_001317186.2:c.-254-2585A>G
NM_004360.5:c.1702A>GMANE SELECT
NP_001304113.1:p.Thr507Ala
NP_001304114.1:p.Thr52Ala
NP_004351.1:p.Thr568Ala
LRG_301t1:c.1702A>G
LRG_301:g.87125A>G
NC_000016.9:g.68853319A>G
NM_004360.3:c.1702A>G
NM_004360.4:c.1702A>G

Protein change:

T507A

Links:

dbSNP: rs1060501242

NCBI 1000 Genomes Browser:

rs1060501242

Molecular consequence:

NM_001317186.2:c.-254-2585A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001317184.2:c.1519A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317185.2:c.154A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.1702A>G - 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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UNVERIFIED_ASMBLY: Pyramimonas propulsa strain AGSB0242 small subunit ribosomal ...
UNVERIFIED_ASMBLY: Pyramimonas propulsa strain AGSB0242 small subunit ribosomal RNA gene, partial sequence; internal transcribed spacer 1, 5.8S ribosomal RNA gene, and internal transcribed spacer 2, complete sequence; and large subunit ribosomal RNA gene, partial sequence
gi|2632235345|gb|OR922727.1|

Nucleotide
Rhynchostegium sp. SH-2008 ITS1 (partial), 5.8S rRNA gene and ITS2 (partial), is...
Rhynchostegium sp. SH-2008 ITS1 (partial), 5.8S rRNA gene and ITS2 (partial), isolate SH442
gi|238654651|emb|FM212670.1|

Nucleotide
Dsc3p [Saccharomyces cerevisiae S288C]
Dsc3p [Saccharomyces cerevisiae S288C]
gi|398365837|ref|NP_014866.3|

Protein
NPBWR2 neuropeptides B and W receptor 2 [Homo sapiens]
NPBWR2 neuropeptides B and W receptor 2 [Homo sapiens]
Gene ID:2832

Gene
2832[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545453	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 36436516, 28492532
SCV003926831	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

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000545453

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 15, 2023)

germline

clinical testing

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

SCV003926831

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]

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000545453.9

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

Description

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 406660). This missense change has been observed in individual(s) with breast cancer (PMID: 36436516). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 568 of the CDH1 protein (p.Thr568Ala).

#	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

From European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto - ERN GENTURIS, SCV003926831.1

#	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 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

Last Updated: Jun 23, 2024

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