NM_007294.3(BRCA1):c.68_69delAG (p.Glu23Valfs) AND Familial cancer of breast

Clinical significance:Pathogenic (Last evaluated: Feb 23, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000056295.6

Allele description

NM_007294.3(BRCA1):c.68_69delAG (p.Glu23Valfs)

Gene:
BRCA1:BRCA1, DNA repair associated [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.3(BRCA1):c.68_69delAG (p.Glu23Valfs)
Other names:
185_186delAG
HGVS:
  • NC_000017.11:g.43124030_43124031delCT
  • NG_005905.2:g.93955_93956delAG
  • NM_007294.3:c.68_69delAG
  • NM_007297.3:c.-20_-19delAG
  • NM_007299.3:c.66_67delAG
  • NM_007300.3:c.66_67delAG
  • NP_009225.1:p.Glu23Valfs
  • NP_009230.2:p.Glu23Valfs
  • NP_009231.2:p.Glu23Valfs
  • LRG_292t1:c.68_69delAG
  • LRG_292:g.93955_93956delAG
  • LRG_292p1:p.Glu23Valfs
  • NC_000017.10:g.41276045_41276046delCT
  • NC_000017.10:g.41276047_41276048delCT
  • NC_000017.11:g.43124028_43124029delCT
  • NG_005905.2:g.93953_93954delAG
  • NM_007294.3:c.66_67del
  • NM_007294.3:c.66_67delAG
  • NM_007294.3:c.68_69del
  • NM_007297.3:c.-22_-21delAG
  • NM_007299.3:c.68_69delAG
  • NR_027676.1:n.227_228delAG
  • NR_027676.1:n.229_230delAG
  • U14680.1:c.66_67delAG
  • U14680.1:n.185_186delAG
  • p.E23VFS*17
  • p.E23VfsX17
  • p.Glu23Valfs*17
  • p.Glu23ValfsX17
  • p.Glu23fs
  • NM_007294.3(BRCA1):c.68_69delAG
  • NM_007294.3:c.68_69delAG(185delAG or 187delAG)
  • NR_027676.1:c.229_230delAG
Nucleotide change:
185delAG
Links:
Breast Cancer Information Core (BIC) (BRCA1): 185&base_change=del AG; OMIM: 113705.0003; dbSNP: rs386833395; dbSNP: rs80357783
NCBI 1000 Genomes Browser:
rs386833395
Allele Frequency:
0.00024(-)
Molecular consequence:
  • NM_007297.3:c.-20_-19delAG - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_007294.3:c.68_69delAG - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_027676.1:n.229_230delAG - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
loss_of_function_variant [Sequence Ontology: SO:0002054]
Observations:
1

Condition(s)

Name:
Familial cancer of breast
Synonyms:
CHEK2-Related Breast Cancer
Identifiers:
MedGen: C0346153; OMIM: 114480

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000086950GeneReviewsno assertion criteria providedpathologic
(Sep 26, 2013)
not providedcuration

SCV000108687GeneDxcriteria provided, single submitter
Pathogenic
(Oct 6, 2014)
germlineclinical testing

Citation Link,

SCV000540943Baylor Miraca Genetics Laboratoriescriteria provided, single submitter
Pathogenic
(Feb 23, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000693502GeneKor MSAno assertion criteria provided
Pathogenic
(Nov 1, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From GeneReviews, SCV000086950.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From GeneDx, SCV000108687.3

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

Description

This mutation is caused by the deletion of two nucleotides (AG) in BRCA1 exon 2, and is denoted c.68_69delAG at the cDNA level using current HGVS nomenclature, or Glu23ValfsX16 at the protein level. The mutation is also known as BRCA1 185delAG or 187delAG and is a founder mutation in the Ashkenazi Jewish population (Struewing 1995). The deletion causes a frameshift, which changes a Glutamic acid to a Valine at codon 23 and creates a premature stop codon at position 16 of the new reading frame. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA1-related cancer risks for women who have not been diagnosed with cancer have been estimated to be 57% - 84% lifetime risk for breast cancer and 24% - 54% lifetime risk for ovarian cancer (Antoniou 2003, Chen 2007, Ford 1998). BRCA1 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Pennington 2013). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA1 mutation include approximately 3% risk for pancreatic cancer (The Breast Cancer Linkage Consortium 1999), a 20% risk for prostate cancer (Thompson 2002), and 4% risk for male breast cancer (Liede 2004). The variant is found in BR-OV-HEREDIC,BRCA1-BRCA2,BRCA-AJ,HIRISK-BR-HEREDIC,HEREDICANCER panel(s).

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

From Baylor Miraca Genetics Laboratories, SCV000540943.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From GeneKor MSA, SCV000693502.1

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

Last Updated: Jul 30, 2018