NM_000059.3(BRCA2):c.8057T>C (p.Leu2686Pro) AND not provided

Clinical significance:Likely pathogenic (Last evaluated: Dec 10, 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:
RCV000479056.1

Allele description [Variation Report for NM_000059.3(BRCA2):c.8057T>C (p.Leu2686Pro)]

NM_000059.3(BRCA2):c.8057T>C (p.Leu2686Pro)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.3(BRCA2):c.8057T>C (p.Leu2686Pro)
HGVS:
  • NC_000013.11:g.32363259T>C
  • NG_012772.3:g.52780T>C
  • NM_000059.3:c.8057T>C
  • NP_000050.2:p.Leu2686Pro
  • LRG_293t1:c.8057T>C
  • LRG_293:g.52780T>C
  • LRG_293p1:p.Leu2686Pro
  • NC_000013.10:g.32937396T>C
  • U43746.1:n.8285T>C
Protein change:
L2686P
Links:
dbSNP: rs28897746
NCBI 1000 Genomes Browser:
rs28897746
Molecular consequence:
  • NM_000059.3:c.8057T>C - 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
SCV000565756GeneDxcriteria provided, single submitter
Likely pathogenic
(May 19, 2016)
germlineclinical testing

Citation Link,

SCV000883517ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Dec 10, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Details of each submission

From GeneDx, SCV000565756.4

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

Description

This variant is denoted BRCA2 c.8057T>C at the cDNA level, p.Leu2686Pro (L2686P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 8285T>C. This variant was observed in an individual diagnosed with Fanconi Anemia who also harbored a pathogenic variant in trans with BRCA2 Leu2686Pro (Dodgshun 2016). This variant was strongly predicted by Lindor et al. (2012) to be likely pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. BRCA2 Leu2686Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2686Pro occurs at a position that is conserved across species and is located in the DNA binding domain, the nuclear export signal motif, and the SHFM1 binding domain (Marston 1999, Yang 2002, Jayesekharan 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA2 Leu2686Pro to be a likely pathogenic variant.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000883517.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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