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NM_004360.5(CDH1):c.2572G>C (p.Asp858His) AND not provided

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
May 22, 2023
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:
RCV000483138.3

Allele description [Variation Report for NM_004360.5(CDH1):c.2572G>C (p.Asp858His)]

NM_004360.5(CDH1):c.2572G>C (p.Asp858His)

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.2572G>C (p.Asp858His)
HGVS:
  • NC_000016.10:g.68833422G>C
  • NG_008021.1:g.101131G>C
  • NM_001317184.2:c.2389G>C
  • NM_001317185.2:c.1024G>C
  • NM_001317186.2:c.607G>C
  • NM_004360.5:c.2572G>CMANE SELECT
  • NP_001304113.1:p.Asp797His
  • NP_001304114.1:p.Asp342His
  • NP_001304115.1:p.Asp203His
  • NP_004351.1:p.Asp858His
  • LRG_301t1:c.2572G>C
  • LRG_301:g.101131G>C
  • NC_000016.9:g.68867325G>C
  • NM_004360.3:c.2572G>C
  • NM_004360.4:c.2572G>C
  • p.D858H
Protein change:
D203H
Links:
dbSNP: rs587782025
NCBI 1000 Genomes Browser:
rs587782025
Molecular consequence:
  • NM_001317184.2:c.2389G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317185.2:c.1024G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317186.2:c.607G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004360.5:c.2572G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000566945GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Uncertain significance
(May 22, 2023) 		germlineclinical testing

Citation Link,

SCV001553603Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000566945.4

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with pancreatic cancer (Hu et al., 2016); This variant is associated with the following publications: (PMID: 15235021, 22850631, 26296696, 26483394)

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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553603.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The CDH1 p.Asp858His variant was identified in 1 of 192 proband chromosomes (frequency: 0.005) from individuals or families with pancreatic cancer (Hu 2016). The variant was also identified in dbSNP (ID: rs587782025) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and Color). The variant was identified in control databases in 2 of 246264 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European in 2 of 111712 chromosomes (freq: 0.00002), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp858 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 provided1not providednot providednot provided

Last Updated: Sep 29, 2024