NM_000059.4(BRCA2):c.7939C>G (p.Leu2647Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 8, 2024
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:: RCV000165643.11

Allele description [Variation Report for NM_000059.4(BRCA2):c.7939C>G (p.Leu2647Val)]

NM_000059.4(BRCA2):c.7939C>G (p.Leu2647Val)

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.7939C>G (p.Leu2647Val)

HGVS:

NC_000013.11:g.32362656C>G
NG_012772.3:g.52177C>G
NM_000059.4:c.7939C>GMANE SELECT
NP_000050.2:p.Leu2647Val
NP_000050.3:p.Leu2647Val
LRG_293t1:c.7939C>G
LRG_293:g.52177C>G
LRG_293p1:p.Leu2647Val
NC_000013.10:g.32936793C>G
NM_000059.3:c.7939C>G
p.L2647V

Protein change:

L2647V

Links:

dbSNP: rs778391123

NCBI 1000 Genomes Browser:

rs778391123

Molecular consequence:

NM_000059.4:c.7939C>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
SCV000216379	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 8, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18451181, 21990134, 23108138, 24323938, 27273131, 29394989, 29884841 Citation Link,
SCV000906564	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 2, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27273131, 33471991, 35190686, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216379

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 8, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000906564

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 2, 2023)

germline

clinical testing

PubMed (4)
[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

Functional assays for classification of BRCA2 variants of uncertain significance.

Farrugia DJ, Agarwal MK, Pankratz VS, Deffenbaugh AM, Pruss D, Frye C, Wadum L, Johnson K, Mentlick J, Tavtigian SV, Goldgar DE, Couch FJ.

Cancer Res. 2008 May 1;68(9):3523-31. doi: 10.1158/0008-5472.CAN-07-1587.

PubMed [citation]

PMID:: 18451181
PMCID:: PMC2936780

A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).

Lindor NM, Guidugli L, Wang X, Vallée MP, Monteiro AN, Tavtigian S, Goldgar DE, Couch FJ.

Hum Mutat. 2012 Jan;33(1):8-21. doi: 10.1002/humu.21627. Epub 2011 Nov 3. Review.

PubMed [citation]

PMID:: 21990134
PMCID:: PMC3242438

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV000216379.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.L2647V variant (also known as c.7939C>G), located in coding exon 16 of the BRCA2 gene, results from a C to G substitution at nucleotide position 7939. The leucine at codon 2647 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in a woman with a personal history of early onset breast cancer (Byers H et al. Eur. J. Hum. Genet., 2016 11;24:1591-1597). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

From Color Diagnostics, LLC DBA Color Health, SCV000906564.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces leucine with valine at codon 2647 in the DNA binding domain 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). This variant has been reported to be functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual affected with breast cancer and in an unaffected individual (PMID: 27273131, 33471991; Leiden Open Variation Database DB-ID BRCA2_003789). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same amino acid position, p.Leu2647Pro, is considered to be disease-causing (ClinVar variation ID: 52443), suggesting that leucine at this position is important for BRCA2 function. 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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