NM_007294.3(BRCA1):c.5467+8G>A AND not provided

Clinical significance:Uncertain significance (Last evaluated: Aug 16, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000588816.5

Allele description [Variation Report for NM_007294.3(BRCA1):c.5467+8G>A]

NM_007294.3(BRCA1):c.5467+8G>A

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.3(BRCA1):c.5467+8G>A
HGVS:
  • NC_000017.11:g.43047635C>T
  • NG_005905.2:g.170349G>A
  • NM_007294.3:c.5467+8G>A
  • NM_007297.4:c.5326+8G>A
  • NM_007298.3:c.2155+8G>A
  • NM_007299.4:c.2081+8G>A
  • NM_007300.4:c.5530+8G>A
  • LRG_292t1:c.5467+8G>A
  • LRG_292:g.170349G>A
  • NC_000017.10:g.41199652C>T
  • U14680.1:n.5586+8G>A
Nucleotide change:
IVS23+8G>A
Links:
Breast Cancer Information Core (BIC) (BRCA1): 5586+8&base_change=G to A; dbSNP: rs80358062
NCBI 1000 Genomes Browser:
rs80358062
Molecular consequence:
  • NM_007294.3:c.5467+8G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007297.4:c.5326+8G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007298.3:c.2155+8G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007299.4:c.2081+8G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007300.4:c.5530+8G>A - intron variant - [Sequence Ontology: SO:0001627]
Functional consequence:
functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000210223GeneDxcriteria provided, single submitter
Uncertain significance
(Nov 29, 2013)
germlineclinical testing

Citation Link,

SCV000600422Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Uncertain significance
(Aug 16, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000699257Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Oct 31, 2016)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

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

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]
PMID:
26467025
PMCID:
PMC4737317

Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.

Judkins T, Hendrickson BC, Deffenbaugh AM, Eliason K, Leclair B, Norton MJ, Ward BE, Pruss D, Scholl T.

Cancer Res. 2005 Nov 1;65(21):10096-103.

PubMed [citation]
PMID:
16267036
See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000210223.10

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

Description

This variant is denoted BRCA1 IVS22+8G>A or c.5467+8G>A and consists of a G>A nucleotide substitution at the +8 position of intron 22 of the BRCA1 gene. Multiple in silico prediction programs predict this variant to create a cryptic splice site that is used instead of the nearby natural donor site. The splicing defect would add 5 bases to the protein and might lead to a change the reading frame; however, it is near to the end of the protein so the clinical significance is unclear. This variant has not, to our knowledge, been published in the literature as pathogenic or benign and is listed twice in BIC as having unknown significance. BRCA1 c.5467+8G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The intronic base is poorly conserved throughout evolution. Based on the currently available information, we cannot assess whether BRCA1 c.5467+8G>A is a pathogenic variant or a benign polymorphism.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000600422.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699257.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: The BRCA1 c.5467+8G>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this substitution along with 2/5 splice prediction tools predicting the variant not to have an impact on normal splicing. This variant was found in 2/121404 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest has been reported in affected individuals via publications with limited information (ie, lack of co-occurrence and cosegregation data). Clinical diagnostic laboratories report this variant with conflicting classifications "benign" or "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "variant of uncertain significance (VUS)."

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

Last Updated: Jun 14, 2021

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