Submissions for variant NM_000059.4(BRCA2):c.8382C>G (p.Phe2794Leu)

gnomAD frequency: 0.00001  dbSNP: rs80359084

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130127	SCV000184959	likely benign	Hereditary cancer-predisposing syndrome	2020-01-23	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766553	SCV000600800	uncertain significance	not provided	2021-07-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000766553	SCV000617126	uncertain significance	not provided	2017-04-07	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8382C>G at the cDNA level, p.Phe2794Leu (F2794L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTG). Using alternate nomenclature, this variant would be defined as BRCA2 8610C>G. Although this variant has not, to our knowledge, been published in the literature as pathogenic or benign, this residue has been predicted to be crucial to maintain proper protein folding (Biswas 2012). BRCA2 Phe2794Leu was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Phe2794Leu occurs at a position that is conserved in mammals and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Phe2794Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130127	SCV001348391	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 2794 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). Functional studies have shown this variant does not impact homology-directed DNA repair (PMID: 29884841, 33609447, 35736817). This variant has been reported in two individual affected with breast cancer (PMID: 32994724, 35402282). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001326297	SCV001517322	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2794 of the BRCA2 protein (p.Phe2794Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 32994724, 35402282). ClinVar contains an entry for this variant (Variation ID: 52570). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000130127	SCV002531940	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	curation
Baylor Genetics	RCV003460618	SCV004213630	uncertain significance	Familial cancer of breast	2023-08-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113922	SCV004845650	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 2794 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). Functional studies have shown this variant does not impact homology-directed DNA repair (PMID: 29884841, 33609447, 35736817). This variant has been reported in two individual affected with breast cancer (PMID: 32994724, 35402282). 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113922	SCV000147351	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000766553	SCV000592188	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Phe2794Leu variant was not identified in probands in the literature but was identified in dbSNP (ID: rs80359084 ) “With uncertain significance allele”, LOVD, the ClinVar database (submitted by Ambry Genetics with a classification of uncertain significance) , the BIC database (2X as a variant with unknown clinical significance). The p.Phe2794Leu is conserved in mammals but not across lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. One in silico study using a protein-likelihood model predicted the variant to be neutral (Karchin 2008). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.