NM_000059.3(BRCA2):c.9976A>T (p.Lys3326Ter) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Benign(4);Likely benign(2) (Last evaluated: Jan 29, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000045926.7

Allele description

NM_000059.3(BRCA2):c.9976A>T (p.Lys3326Ter)

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.9976A>T (p.Lys3326Ter)
HGVS:
  • NC_000013.11:g.32398489A>T
  • NG_012772.3:g.88010A>T
  • NM_000059.3:c.9976A>T
  • NP_000050.2:p.Lys3326Ter
  • LRG_293t1:c.9976A>T
  • LRG_293:g.88010A>T
  • LRG_293p1:p.Lys3326Ter
  • NC_000013.10:g.32972626A>T
  • NP_000050.2:p.Lys3326*
  • U43746.1:n.10204A>T
  • p.K3326*
Nucleotide change:
10204A>T
Protein change:
K3326*
Links:
dbSNP: rs11571833
GMAF:
0.0044(T), 11571833
NCBI 1000 Genomes Browser:
rs11571833
Allele Frequency:
0.0065, GO-ESP
Molecular consequence:
  • NM_000059.3:c.9976A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer
Identifiers:
MedGen: C0677776; Orphanet: 145; OMIM: PS604370

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000073939Invitaecriteria provided, single submitter
Benign
(Jan 29, 2017)
germlineclinical testing

Citation Link,

SCV000212199CSER_CC_NCGL; University of Washington Medical Center - CSER - NEXT Medicine variant annotationcriteria provided, single submitter
Benign
(Mar 11, 2015)
germlineresearch

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

SCV000219429CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontariocriteria provided, single submitter
Likely benign
(Jan 20, 2016)
germlineclinical testing

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

SCV000257622Division of Genomic Diagnostics,The Children's Hospital of Philadelphiacriteria provided, single submitter
Benign
(Jul 9, 2015)
unknownclinical testing

DGD_Variant_Analysis_Guidelines.docx,

Citation Link,

SCV000383808Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Jun 14, 2016)
germlineclinical testing

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

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000494404Laboratory Corporation of Americacriteria provided, single submitter
Benign
(Aug 12, 2016)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]
PMID:
25637381
PMCID:
PMC4352885

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
See all PubMed Citations (12)

Details of each submission

From Invitae, SCV000073939.6

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

From CSER_CC_NCGL; University of Washington Medical Center - CSER - NEXT Medicine variant annotation, SCV000212199.1

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

From CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario, SCV000219429.2

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

Description

Interpretation was last updated within 1 year from 1/20/2016 1:08 PM

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

From Division of Genomic Diagnostics,The Children's Hospital of Philadelphia, SCV000257622.2

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

From Illumina Clinical Services Laboratory,Illumina, SCV000383808.2

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

From Laboratory Corporation of America, SCV000494404.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: The BRCA2 c.9976A>T (p.Lys3326X) variant results in a termination codon at the penultimate exon, predicted to cause a truncation of the last 93 amino acids. This variant is not expected to affect any known domain (InterPro) and no truncations downstream of this position have been reported to be pathogenic in literature and databases. This variant was found in 2327/296226 control chromosomes (including 8 homozygotes) at a frequency of 0.0078555, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this variant is likely a benign polymorphism. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as benign (14)/likely benign (1). Available family, co-occurrence and functional data also show that it is not a disease causing variant. Despite these, this variant is found at considerably high frequency, especially in patients with breast and/or ovarian cancer, raising a possibilty that it may be a risk variant. Using weighted logistic regression, Meeks et al 2016 analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Other adjustments in the study were adjustment for attained age, consortium study site, and principal components of population structure. From the study, weighted ORs for invasive breast cancer and ovarian cancers were 1.28 (confidence interval 1.17-1.4; P-value=3.84x10e-3) and 1.26 (confidence interval 1.1-1.43; P-value=3.84x10e-3), respectively. The authors conclude that this study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Hence this variant is a risk allele which attributes a significant but a "low" risk in development of breast or ovarian cancer. In addition, other genetic/lifestyle/environmental factors may also be playing a part in elevation of risk. Taken together, this variant is classified as Benign for HBOC and/or variant of uncertain significance for HBOCrisk,

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

Last Updated: Nov 24, 2017

Support Center