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

Recent activity

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Cystadenocarcinoma, Serous
Cystadenocarcinoma, Serous
A malignant cystic or semicystic neoplasm. It often occurs in the ovary and usually bilaterally. The external surface is usually covered with papillary excrescences. Microscop...<br/>Year introduced: 1994

MeSH
D018284 (1)
MeSH
Homo sapiens L-pipecolic acid oxidase (LPIPOX) mRNA, complete cds
Homo sapiens L-pipecolic acid oxidase (LPIPOX) mRNA, complete cds
gi|7157902|gb|AF134593.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000666088	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jan 11, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28135145, 32444794, 33471991, 33558524 Citation Link,
SCV000906584	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28135145, 32444794, 33471991, 33558524, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000666088

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jan 11, 2022)

germline

clinical testing

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

Citation Link,

SCV000906584

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 25, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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