NM_000059.3(BRCA2):c.1096T>G (p.Leu366Val) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jun 12, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000074510.6

Allele description [Variation Report for NM_000059.3(BRCA2):c.1096T>G (p.Leu366Val)]

NM_000059.3(BRCA2):c.1096T>G (p.Leu366Val)

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.1096T>G (p.Leu366Val)
Other names:
p.L366V:TTA>GTA
HGVS:
  • NC_000013.11:g.32332574T>G
  • NG_012772.3:g.22095T>G
  • NM_000059.3:c.1096T>G
  • NP_000050.2:p.Leu366Val
  • LRG_293t1:c.1096T>G
  • LRG_293:g.22095T>G
  • LRG_293p1:p.Leu366Val
  • NC_000013.10:g.32906711T>G
  • p.L366V
Nucleotide change:
1324T>G
Protein change:
L366V
Links:
dbSNP: rs587779357
NCBI 1000 Genomes Browser:
rs587779357
Molecular consequence:
  • NM_000059.3:c.1096T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000108595GeneDxcriteria provided, single submitter
Likely benign
(Jul 7, 2016)
germlineclinical testing

Citation Link,

SCV000694507Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jun 12, 2021)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Rapid mutation detection in complex genes by heteroduplex analysis with capillary array electrophoresis.

Velasco E, Infante M, Durán M, Esteban-Cardeñosa E, Lastra E, García-Girón C, Miner C.

Electrophoresis. 2005 Jun;26(13):2539-52.

PubMed [citation]
PMID:
15937982

EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients.

Caux-Moncoutier V, Castéra L, Tirapo C, Michaux D, Rémon MA, Laugé A, Rouleau E, De Pauw A, Buecher B, Gauthier-Villars M, Viovy JL, Stoppa-Lyonnet D, Houdayer C.

Hum Mutat. 2011 Mar;32(3):325-34. doi: 10.1002/humu.21414. Epub 2011 Feb 8.

PubMed [citation]
PMID:
21120943
See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000108595.12

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694507.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: BRCA2 c.1096T>G (p.Leu366Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 2/5 splice prediction tools predict that this variant may create a novel 3' splicing acceptor site. However, one study showed that aberrant splicing was not found in a patient who carries this variant (Thomassen_2011). The variant allele was found at a frequency of 2.8e-05 in 249022 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096T>G has been reported in the literature in individuals affected with breast and ovarian cancer (example, Velasco_2005, Thomassen_2011, Silva_2014, Caux-Montcoutier_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3 and VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Jun 22, 2021

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