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NM_000059.4(BRCA2):c.8699A>T (p.Asp2900Val) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jul 25, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000564657.12

Allele description [Variation Report for NM_000059.4(BRCA2):c.8699A>T (p.Asp2900Val)]

NM_000059.4(BRCA2):c.8699A>T (p.Asp2900Val)

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.8699A>T (p.Asp2900Val)
HGVS:
  • NC_000013.11:g.32376736A>T
  • NG_012772.3:g.66257A>T
  • NM_000059.4:c.8699A>TMANE SELECT
  • NP_000050.2:p.Asp2900Val
  • NP_000050.3:p.Asp2900Val
  • LRG_293t1:c.8699A>T
  • LRG_293:g.66257A>T
  • LRG_293p1:p.Asp2900Val
  • NC_000013.10:g.32950873A>T
  • NM_000059.3:c.8699A>T
Nucleotide change:
8927A>T
Protein change:
D2900V
Links:
dbSNP: rs398122712
NCBI 1000 Genomes Browser:
rs398122712
Molecular consequence:
  • NM_000059.4:c.8699A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000666088Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely benign
(Jan 11, 2022)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000906584Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jul 25, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S.

J Clin Oncol. 2017 Apr 1;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012. Epub 2017 Jan 30.

PubMed [citation]
PMID:
28135145
PMCID:
PMC5455355

High-throughput functional evaluation of BRCA2 variants of unknown significance.

Ikegami M, Kohsaka S, Ueno T, Momozawa Y, Inoue S, Tamura K, Shimomura A, Hosoya N, Kobayashi H, Tanaka S, Mano H.

Nat Commun. 2020 May 22;11(1):2573. doi: 10.1038/s41467-020-16141-8.

PubMed [citation]
PMID:
32444794
PMCID:
PMC7244490
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000666088.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

From Color Diagnostics, LLC DBA Color Health, SCV000906584.4

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

Description

This missense variant replaces aspartic acid with valine at codon 2900 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown this variant does not impact sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in individuals affected with breast cancer (PMID: 33471991, 33558524) and colorectal cancer (PMID: 28135145). This variant has been identified in 1/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024