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NM_004360.5(CDH1):c.1633C>T (p.Arg545Trp) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Oct 28, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001358029.5

Allele description [Variation Report for NM_004360.5(CDH1):c.1633C>T (p.Arg545Trp)]

NM_004360.5(CDH1):c.1633C>T (p.Arg545Trp)

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.1633C>T (p.Arg545Trp)
HGVS:
  • NC_000016.10:g.68819347C>T
  • NG_008021.1:g.87056C>T
  • NM_001317184.2:c.1450C>T
  • NM_001317185.2:c.85C>T
  • NM_001317186.2:c.-254-2654C>T
  • NM_004360.5:c.1633C>TMANE SELECT
  • NP_001304113.1:p.Arg484Trp
  • NP_001304114.1:p.Arg29Trp
  • NP_004351.1:p.Arg545Trp
  • LRG_301t1:c.1633C>T
  • LRG_301:g.87056C>T
  • NC_000016.9:g.68853250C>T
  • NM_004360.3:c.1633C>T
  • NM_004360.4:c.1633C>T
Protein change:
R29W
Links:
dbSNP: rs863224727
NCBI 1000 Genomes Browser:
rs863224727
Molecular consequence:
  • NM_001317186.2:c.-254-2654C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001317184.2:c.1450C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317185.2:c.85C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004360.5:c.1633C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001553661Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

SCV002012643GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Uncertain significance
(Oct 28, 2019) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553661.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The CDH1 p.Arg545Trp variant was not identified in the literature. The variant was identified in dbSNP (ID: rs863224727) as “With Uncertain significance allele” and ClinVar (as uncertain significance by Invitae and one other submitter). The variant was identified in control databases in 1 of 246266 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 1 of 30778 chromosomes (freq: 0.000032), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, or European Finnish populations. The variant was identified by our laboratory with a co-occurring, pathogenic BRCA2 variant (c.5946del, p.Ser1982Argfs*22), increasing the likelihood that the CDH1 p.Arg545Trp variant does not have clinical significance. The p.Arg545 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV002012643.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with breast cancer (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024