Submissions for variant NM_000059.4(BRCA2):c.2135T>C (p.Leu712Pro)

dbSNP: rs80358490

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000043949	SCV000071962	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131476	SCV000186463	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	The p.L712P variant (also known as c.2135T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 2135. The leucine at codon 712 is replaced by proline, an amino acid with similar properties. This alteration was reported in a a cohort of 1236 patients with soft-tissue sarcomas and 1312 patients with leiomyosarcomas (Seligson ND et al. Oncologist, 2019 07;24:973-979). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000590581	SCV000210282	uncertain significance	not provided	2019-01-07	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.2135T>C at the cDNA level, p.Leu712Pro (L712P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu712Pro in large population cohorts (Lek 2016). BRCA2 Leu712Pro is located not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether BRCA2 Leu712Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590581	SCV000694592	uncertain significance	not provided	2016-07-26	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2135T>C (p.Leu712Pro) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a benign outcome. This variant is outside of known functional domains in BRCA2 protein. This variant is absent in approximately 120854 control chromosomes from ExAC. This variant has been reported in at least one clinical sample in a study (Mattocks_2010), without strong evidence for or against pathogenicity. It has also been reported in one sample by BIC without co-occurrence with another deleterious variant in BRCA1/2. But in one of two samples reported in UMD, this variant co-occured with another deleterious variant BRCA2 p.Tyr1894X. Although the possibility that this patient had Faconi Anemia can not be ruled out, it is more likely that the variant of interest is not pathogenic. Multiple clinical diagnostic laboratories and a reputable database (UMD) have classified this variant as uncertain significance. Taken all lines of evidence together, this variant is classified as VUS-possibly benign.
Counsyl	RCV000113019	SCV000786270	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590581	SCV000889003	uncertain significance	not provided	2018-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131476	SCV000906889	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 712 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 prostate cancer (PMID: 32268276). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 2/53461 unaffected controls (OR=1.326 (95%CI 0.222 to 7.938)) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001655). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131476	SCV003846521	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000113019	SCV004847013	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 712 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 prostate cancer (PMID: 32268276). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 2/53461 unaffected controls (OR=1.326 (95%CI 0.222 to 7.938)) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001655). 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)	RCV000113019	SCV000146010	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing