Submissions for variant NM_000059.4(BRCA2):c.8915T>G (p.Leu2972Trp)

gnomAD frequency: 0.00001  dbSNP: rs80359142

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212282	SCV000210488	uncertain significance	not provided	2015-07-13	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8915T>G at the cDNA level, p.Leu2972Trp (L2972W) at the protein level, and results in the change of a Leucine to a Tryptophan (TTG>TGG). Using alternate nomenclature, this variant would be defined as BRCA2 9143T>G. This variant has been included in one functional study where it was determined not to influence the interaction with Filamin A (Mondal 2012). BRCA2 Leu2972Trp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Leucine and Tryptophan differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2972Trp occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within the DNA binding domain (Borg 2010). Both in house in silico analyses and published computational models predict that this variant is probably damaging to protein structure and function (Karchin 2008). Based on currently available information, it is unclear whether BRCA2 Leu2972Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000215767	SCV000274114	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	The p.L2972W variant (also known as c.8915T>G), located in coding exon 21 of the BRCA2 gene, results from a T to G substitution at nucleotide position 8915. The leucine at codon 2972 is replaced by tryptophan, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Li JY et al. Int J Cancer, 2019 Jan;144:281-289; Santonocito C et al. Cancers (Basel), 2020 May;12:). 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.
Color Diagnostics, LLC DBA Color Health	RCV000215767	SCV000684006	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with tryptophan at codon 2972 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 reported that this variant has a partial or no impact on BRCA2 function in homology-mediated repair assays (PMID: 29394989, 35736817) and inconclusive impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in at least three individuals affected with breast and/or ovarian cancer, two individuals affected with prostate cancer, and at least seven unaffected individuals (PMID: 29752822, 32438681, 32853339, 33471991; Leiden Open Variation Database DB-ID BRCA2_000383). This variant has been identified in 8/249366 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346965	SCV001541203	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 2972 of the BRCA2 protein (p.Leu2972Trp). This variant is present in population databases (rs80359142, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or prostate cancer (PMID: 29752822, 32438681, 32853339). ClinVar contains an entry for this variant (Variation ID: 52700). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 22771033). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222370	SCV002500368	uncertain significance	not specified	2022-03-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8915T>G (p.Leu2972Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249366 control chromosomes (gnomAD). c.8915T>G has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Santonocito_2020, Li_2019) and prostate cancer (e.g. Darst_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 7/53461 controls (Dorling_2021 through LOVD). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant had a partial effect on homology directed DNA repair activity (Guidugli_2018), but resulted in filamin A binding activity to the wild-type(Mondal_2012). Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002222370	SCV002551838	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460626	SCV004216028	uncertain significance	Familial cancer of breast	2023-07-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212282	SCV004220632	uncertain significance	not provided	2023-07-20	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with a personal history of breast and/or ovarian cancer (PMID: 32438681 (2020), 31227342 (2019)), or prostate cancer (PMID: 32853339 (2021)), or at high risk of hereditary breast cancer (PMID: 29752822 (2018)). In a large scale breast cancer association study, the variant was observed in breast cancer cases as well as unaffected control individuals (PMID: 33471991 (2021)). Experimental studies have demonstrated this variant has a neutral (PMID: 35736817 (2022), 22771033 (2012)) or intermediate (PMID: 29394989 (2018)) effect on BRCA2 protein function. The frequency of this variant in the general population, 0.000071 (8/112520 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000114014	SCV004846093	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with tryptophan at codon 2972 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 reported that this variant has a partial or no impact on BRCA2 function in homology-mediated repair assays (PMID: 29394989, 35736817) and inconclusive impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in at least three individuals affected with breast and/or ovarian cancer, two individuals affected with prostate cancer, and at least seven unaffected individuals (PMID: 29752822, 32438681, 32853339, 33471991; Leiden Open Variation Database DB-ID BRCA2_000383). This variant has been identified in 8/249366 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212282	SCV005196952	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000114014	SCV005431460	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-07-17	criteria provided, single submitter	clinical testing	The following ACMG criteria is used: BS1_Supporting; BP4 (BayesDel score 0.12), BS3 (PMID: 38417439)
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114014	SCV000147485	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-01-17	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000114014	SCV004243839	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing