Submissions for variant NM_000059.4(BRCA2):c.9821T>G (p.Leu3274Trp)

gnomAD frequency: 0.00001  dbSNP: rs431825380

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131538	SCV000186533	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-19	criteria provided, single submitter	clinical testing	The p.L3274W variant (also known as c.9821T>G), located in coding exon 26 of the BRCA2 gene, results from a T to G substitution at nucleotide position 9821. The leucine at codon 3274 is replaced by tryptophan, an amino acid with similar properties. This alteration has been reported in 1/260 Japanese high risk breast/ovarian probands (Nakamura S et al. Breast Cancer 2015 Sep; 22(5):462-8), 1/830 Japanese patients who underwent BRCA1/2 testing (Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457), as a germline variant in a cohort of 1063 HDR deficient epithelial ovarian cancers (Cunningham JM et al. Sci Rep, 2014 Feb;4:4026), and in a patient with duodenal adenocarcinoma from a cohort of 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with nonneoplastic diseases who underwent pancreatic resection (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477120	SCV000549842	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-27	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 3274 of the BRCA2 protein (p.Leu3274Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer and duodenal adenocarcinoma (PMID: 24249303, 24504028, 28767289, 29176636). ClinVar contains an entry for this variant (Variation ID: 96889). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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	RCV000590068	SCV000695273	uncertain significance	not provided	2017-08-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9821T>G (p.Leu3274Trp) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant is absent in 30962 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. However, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)."
Counsyl	RCV000083010	SCV000786202	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-03-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590068	SCV000889193	uncertain significance	not provided	2018-05-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131538	SCV000906825	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with tryptophan at codon 3274 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 one individual each affected with ovarian cancer (PMID: 24504028) and pancreatic cancer with family history of breast cancer (PMID: 28767289). This variant also has been reported in a family affected with breast/ovarian cancer (PMID: 24249303). 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.
GeneDx	RCV000590068	SCV002498855	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history of breast or ovarian cancer (PMID: 24504028, 24249303, 28767289, 29176636); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 10049T>G; This variant is associated with the following publications: (PMID: 24249303, 28767289, 24504028, 29176636, 32377563, 29884841)
Baylor Genetics	RCV003460762	SCV004213691	uncertain significance	Familial cancer of breast	2024-03-26	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083010	SCV000115084	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-09-03	no assertion criteria provided	clinical testing