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NM_000059.4(BRCA2):c.6446_6450del (p.Ile2149fs) AND not provided

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Oct 1, 2020
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:
RCV001582541.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.6446_6450del (p.Ile2149fs)]

NM_000059.4(BRCA2):c.6446_6450del (p.Ile2149fs)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.6446_6450del (p.Ile2149fs)
HGVS:
  • NC_000013.10:g.32914937_32914941del
  • NC_000013.11:g.32340801_32340805del
  • NG_012772.3:g.30322_30326del
  • NM_000059.4:c.6446_6450delMANE SELECT
  • NP_000050.3:p.Ile2149fs
  • LRG_293:g.30322_30326del
  • NC_000013.10:g.32914937_32914941del
  • NC_000013.10:g.32914938_32914942del
  • NC_000013.10:g.32914938_32914942delTTAAA
  • NM_000059.3:c.6446_6450delTTAAA
  • NM_000059.4:c.6446_6450del
  • U43746.1:n.6674_6678delTTAAA
  • p.I2149Sfs*25
Nucleotide change:
6674del5
Links:
Breast Cancer Information Core (BIC) (BRCA2): 6674&base_change=del TTAAA; dbSNP: rs80359593
NCBI 1000 Genomes Browser:
rs80359593
Molecular consequence:
  • NM_000059.4:c.6446_6450del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001473221ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Pathogenic
(Aug 5, 2019) 		germlineclinical testing

Citation Link,

SCV001820107GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Pathogenic
(Oct 1, 2020) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473221.1

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

Description

The BRCA2 c.6446_6450delTTAAA; p.Ile2149fs variant (rs80359593), also known as 6674del5, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancers (Dworkin 2009, Kanke 2017, Kwong 2016, Lubinski 2004, Nakamura 2015). This variant is reported in ClinVar (Variation ID: 52102), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several other downstream truncating variants have been reported in individuals with breast and ovarian cancers and are considered pathogenic Kwong 2016, Lubinski 2004, Nakamura 2015). Based on available information, this variant is considered to be pathogenic. References: Dworkin AM et al. Methylation not a frequent "second hit" in tumors with germline BRCA mutations. Fam Cancer. 2009;8(4):339-46. Kanke Y et al. Gene aberration profile of tumors of adolescent and young adult females. Oncotarget. 2017 Dec 29;9(5):6228-6237. Kwong A et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016 Jan;53(1):15-23. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Nakamura S et al. Prevalence and differentiation of hereditary breast and ovarian cancers in Japan. Breast Cancer. 2015 Sep;22(5):462-8.

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

From GeneDx, SCV001820107.1

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with BRCA2-related cancers (Lubinksi 2004, Dworkin 2009, Foley 2015, Nakamura 2015, Kanke 2018, Momozawa 2018); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6445_6449del5, 6674del5, or 6674_6678delTTAAA; This variant is associated with the following publications: (PMID: 31214711, 29176636, 19340607, 20858050, 24249303, 26023681, 26187060, 29464067, 30287823, 15131399)

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

Last Updated: Nov 24, 2024