NM_000059.4(BRCA2):c.7879A>T (p.Ile2627Phe) AND not provided

Clinical significance:Pathogenic (Last evaluated: Nov 1, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000218666.4

Allele description

NM_000059.4(BRCA2):c.7879A>T (p.Ile2627Phe)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.7879A>T (p.Ile2627Phe)
HGVS:
  • NC_000013.11:g.32362596A>T
  • NG_012772.3:g.52117A>T
  • NM_000059.3:c.7879A>T
  • NM_000059.4:c.7879A>T
  • NP_000050.2:p.Ile2627Phe
  • NP_000050.3:p.Ile2627Phe
  • LRG_293t1:c.7879A>T
  • LRG_293:g.52117A>T
  • NC_000013.10:g.32936733A>T
  • U43746.1:n.8107A>T
  • p.I2627F
Nucleotide change:
8107A>T
Protein change:
I2627F
Links:
dbSNP: rs80359014
NCBI 1000 Genomes Browser:
rs80359014
Molecular consequence:
  • NM_000059.3:c.7879A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000059.4:c.7879A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000278877GeneDxcriteria provided, single submitter
Pathogenic
(Aug 22, 2017)
germlineclinical testing

Citation Link,

SCV000296832GeneKor MSAcriteria provided, single submitter
Pathogenic
(Nov 1, 2017)
germlineclinical testing

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

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

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 GeneDx, SCV000278877.9

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

Description

This variant is denoted BRCA2 c.7879A>T at the cDNA level, p.Ile2627Phe (I2627F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATC>TTC). Using alternate nomenclature, this variant has been previously published as BRCA2 8107A>T. BRCA2 Ile2627Phe has been observed in multiple breast/ovarian cancer families (Spitzer 2000, Balabas 2010, Stegel 2011, Lee 2014, Meisel 2017), and was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies demonstrated that BRCA2 Ile2627Phe displayed both reduced homology directed repair activity and an increase in centriole amplification when compared to wild-type, suggesting a disruption of BRCA2 function (Farrugia 2008, Guidugli 2013). BRCA2 Ile2627Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2627Phe occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, we consider BRCA2 Ile2627Phe to be pathogenic.

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

From GeneKor MSA, SCV000296832.2

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

Last Updated: Apr 17, 2020

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