NM_000059.4(BRCA2):c.8808G>C (p.Leu2936Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 7, 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:: RCV000130654.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.8808G>C (p.Leu2936Phe)]

NM_000059.4(BRCA2):c.8808G>C (p.Leu2936Phe)

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.8808G>C (p.Leu2936Phe)

HGVS:

NC_000013.11:g.32379370G>C
NG_012772.3:g.68891G>C
NM_000059.4:c.8808G>CMANE SELECT
NP_000050.2:p.Leu2936Phe
NP_000050.3:p.Leu2936Phe
LRG_293t1:c.8808G>C
LRG_293:g.68891G>C
LRG_293p1:p.Leu2936Phe
NC_000013.10:g.32953507G>C
NM_000059.3:c.8808G>C
U43746.1:n.9036G>C
p.L2936F

Protein change:

L2936F

Links:

dbSNP: rs80359138

NCBI 1000 Genomes Browser:

rs80359138

Molecular consequence:

NM_000059.4:c.8808G>C - 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
SCV000185539	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 7, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19043619, 19491284 Citation Link,
SCV001342503	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19491284, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185539

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 7, 2023)

germline

clinical testing

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

Citation Link,

SCV001342503

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 17, 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

Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.

Karchin R, Agarwal M, Sali A, Couch F, Beattie MS.

Cancer Inform. 2008;6:203-16. Epub 2008 Apr 18.

PubMed [citation]

PMID:: 19043619
PMCID:: PMC2587343

Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and risk of secondary malignancies across diverse racial groups.

Haffty BG, Choi DH, Goyal S, Silber A, Ranieri K, Matloff E, Lee MH, Nissenblatt M, Toppmeyer D, Moran MS.

Ann Oncol. 2009 Oct;20(10):1653-9. doi: 10.1093/annonc/mdp051. Epub 2009 Jun 2.

PubMed [citation]

PMID:: 19491284

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000185539.8

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

Description

The p.L2936F variant (also known as c.8808G>C), located in coding exon 21 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8808. The leucine at codon 2936 is replaced by phenylalanine, an amino acid with highly similar properties. In a study of 333 patients with breast cancer diagnosed under age 45, this alteration was detected in one patient of African American ancestry (Haffty BG et al. Ann. Oncol. 2009 Oct;20:1653-9). Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration is predicted to be neutral (Karchin R et al. Cancer Inform, 2008 Apr;6:203-16). 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

From Color Diagnostics, LLC DBA Color Health, SCV001342503.2

#	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 leucine with phenylalanine at codon 2936 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 19491284). This variant has been identified in 1/250818 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: Nov 10, 2024

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