NM_004360.5(CDH1):c.393C>T (p.Ser131=) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Likely benign (5 submissions)
Last evaluated:: Jan 9, 2024
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:: RCV000989619.17

Allele description [Variation Report for NM_004360.5(CDH1):c.393C>T (p.Ser131=)]

NM_004360.5(CDH1):c.393C>T (p.Ser131=)

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.393C>T (p.Ser131=)

HGVS:

NC_000016.10:g.68808429C>T
NG_008021.1:g.76138C>T
NM_001317184.2:c.393C>T
NM_001317185.2:c.-1223C>T
NM_001317186.2:c.-1427C>T
NM_004360.5:c.393C>TMANE SELECT
NP_001304113.1:p.Ser131=
NP_004351.1:p.Ser131=
LRG_301t1:c.393C>T
LRG_301:g.76138C>T
NC_000016.9:g.68842332C>T
NM_004360.3:c.393C>T
NM_004360.4:c.393C>T
p.S131S

Links:

dbSNP: rs145430811

NCBI 1000 Genomes Browser:

rs145430811

Molecular consequence:

NM_001317185.2:c.-1223C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1427C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.393C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_004360.5:c.393C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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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PREDICTED: Homo sapiens protein phosphatase 1 regulatory subunit 9A (PPP1R9A), t...
PREDICTED: Homo sapiens protein phosphatase 1 regulatory subunit 9A (PPP1R9A), transcript variant X36, mRNA
gi|2217367777|ref|XM_047420595.1|

Nucleotide
CBXT3532.b1 NICHD_XGC_trop_25 Xenopus tropicalis cDNA clone IMAGE:8885613 5', mR...
CBXT3532.b1 NICHD_XGC_trop_25 Xenopus tropicalis cDNA clone IMAGE:8885613 5', mRNA sequence
gi|133807474|gnl|dbEST|45237081|gb| 121.1|

Nucleotide
ARSK [Gavia stellata]
ARSK [Gavia stellata]
Gene ID:104253728

Gene
SPAM1 [Parus major]
SPAM1 [Parus major]
Gene ID:107204979

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000259850	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 9, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001140132	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001279850	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV001552495	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely benign	unknown	clinical testing
SCV003927042	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))	Likely benign (Aug 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30311375, 36436516

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	2	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000259850.11

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

#	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 Mendelics, SCV001140132.1

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

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

From Illumina Laboratory Services, Illumina, SCV001279850.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552495.1

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

Description

The CDH1 p.Ser131= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs145430811) as "With Likely benign allele", and in ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and Prevention Genetics). The variant was identified in 29 of 277130 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 28 of 126628 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Ser131= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	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, SCV003927042.1

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

Description

"2 families not fulfilling 2020 HDGC criteria-Familial history of breast cancer"

PubMed [ID: 36436516]

Description

PS4_Supporting; BP4; BP7 (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	2	not provided

Last Updated: Sep 29, 2024

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