NM_000059.4(BRCA2):c.8686C>T (p.Arg2896Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 29, 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:: RCV000223550.8

Allele description [Variation Report for NM_000059.4(BRCA2):c.8686C>T (p.Arg2896Cys)]

NM_000059.4(BRCA2):c.8686C>T (p.Arg2896Cys)

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.8686C>T (p.Arg2896Cys)

HGVS:

NC_000013.11:g.32376723C>T
NG_012772.3:g.66244C>T
NM_000059.4:c.8686C>TMANE SELECT
NP_000050.2:p.Arg2896Cys
NP_000050.3:p.Arg2896Cys
LRG_293t1:c.8686C>T
LRG_293:g.66244C>T
LRG_293p1:p.Arg2896Cys
NC_000013.10:g.32950860C>T
NM_000059.3:c.8686C>T

Protein change:

R2896C

Links:

dbSNP: rs373203204

NCBI 1000 Genomes Browser:

rs373203204

Molecular consequence:

NM_000059.4:c.8686C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000275209	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] 27930734, 28726806, 32444794, 33471991 Citation Link,
SCV001359808	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 29, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32444794, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000275209

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,

SCV001359808

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 29, 2023)

germline

clinical testing

PubMed (2)
[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

Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records.

He KY, Zhao Y, McPherson EW, Li Q, Xia F, Weng C, Wang K, He MM.

PLoS One. 2016;11(12):e0167847. doi: 10.1371/journal.pone.0167847.

PubMed [citation]

PMID:: 27930734
PMCID:: PMC5145192

Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR).

Lebo MS, Zakoor KR, Chun K, Speevak MD, Waye JS, McCready E, Parboosingh JS, Lamont RE, Feilotter H, Bosdet I, Tucker T, Young S, Karsan A, Charames GS, Agatep R, Spriggs EL, Chisholm C, Vasli N, Daoud H, Jarinova O, Tomaszewski R, Hume S, et al.

Genet Med. 2018 Mar;20(3):294-302. doi: 10.1038/gim.2017.80. Epub 2017 Jul 20.

PubMed [citation]

PMID:: 28726806

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000275209.7

#	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, SCV001359808.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces arginine with cysteine at codon 2896 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental functional study has shown that cells expressing this variant are not sensitive to PARP inhibitors or carboplatin in a cell viability assay, indicating the variant impact is neutral (PMID: 32444794). This variant has not been reported in individuals affected with BRCA2-related cancer in the literature. This variant has been identified in 5/251298 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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