Submissions for variant NM_000059.4(BRCA2):c.7055C>T (p.Pro2352Leu)

gnomAD frequency: 0.00001  dbSNP: rs80358934

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045131	SCV000073144	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2352 of the BRCA2 protein (p.Pro2352Leu). This variant is present in population databases (rs80358934, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 52258). 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.
Ambry Genetics	RCV000222667	SCV000274877	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.P2352L variant (also known as c.7055C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7055. The proline at codon 2352 is replaced by leucine, an amino acid with similar properties. 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.
Counsyl	RCV000113699	SCV000488167	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000588738	SCV000566369	uncertain significance	not provided	2023-02-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 7283C>T; Observed in individuals with breast cancer (Warren et al., 2011); This variant is associated with the following publications: (PMID: 20167696, 29884841, 21520333, 32377563, 21741379)
Color Diagnostics, LLC DBA Color Health	RCV000222667	SCV000683847	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2352 of the BRCA2 protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250862 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588738	SCV000695032	uncertain significance	not provided	2016-07-15	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7055C>T (p.Pro2352Leu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Pro2352 is not located in a known functional domain of Breast cancer type 2 susceptibility protein. This variant was found in 1/121010 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113699	SCV000744509	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588738	SCV001469450	uncertain significance	not provided	2020-07-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477151	SCV002784443	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-11-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588738	SCV002822075	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA2: PM2
Baylor Genetics	RCV003460605	SCV004216006	uncertain significance	Familial cancer of breast	2023-07-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493424	SCV004243058	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113699	SCV000147011	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113699	SCV000733292	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588738	SCV001958342	uncertain significance	not provided		no assertion criteria provided	clinical testing