NM_000059.4(BRCA2):c.9805A>G (p.Arg3269Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 2, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000582462.7

Allele description [Variation Report for NM_000059.4(BRCA2):c.9805A>G (p.Arg3269Gly)]

NM_000059.4(BRCA2):c.9805A>G (p.Arg3269Gly)

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.9805A>G (p.Arg3269Gly)

HGVS:

NC_000013.11:g.32398318A>G
NG_012772.3:g.87839A>G
NM_000059.4:c.9805A>GMANE SELECT
NP_000050.2:p.Arg3269Gly
NP_000050.3:p.Arg3269Gly
LRG_293t1:c.9805A>G
LRG_293:g.87839A>G
LRG_293p1:p.Arg3269Gly
NC_000013.10:g.32972455A>G
NM_000059.3:c.9805A>G

Protein change:

R3269G

Links:

dbSNP: rs1555289964

NCBI 1000 Genomes Browser:

rs1555289964

Molecular consequence:

NM_000059.4:c.9805A>G - 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
SCV000689231	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32444794, 25741868
SCV002694987	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000689231

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 2, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002694987

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 2, 2023)

germline

clinical testing

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

Citation Link

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

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

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

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000689231.4

#	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 glycine at codon 3269 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). A functional study has shown that this variant protein does not increase the sensitivity to PARP inhibitors in mammalian cells when compared to the wild-type protein (PMID: 32444794). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified 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

From Ambry Genetics, SCV002694987.2

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

Description

The p.R3269G variant (also known as c.9805A>G), located in coding exon 26 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9805. The arginine at codon 3269 is replaced by glycine, an amino acid with dissimilar properties. This alteration was reported as benign based on sensitivity to PARP inhibitors in a high-throughput in vitro assay performed in a human colorectal adenoma cell line (Ikegami M et al. Nat Commun, 2020 May;11:2573). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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