Submissions for variant NM_000059.4(BRCA2):c.1355T>C (p.Leu452Pro)

dbSNP: rs753512842

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Michigan Medical Genetics Laboratories, University of Michigan	RCV000211025	SCV000267744	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000766590	SCV000567871	uncertain significance	not provided	2015-09-10	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.1355T>C at the cDNA level, p.Leu452Pro (L452P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 1583T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu452Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu452Pro occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Leu452Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766590	SCV000600475	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	In a large scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000004 (1/247608 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.
Ambry Genetics	RCV000568425	SCV000668814	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-13	criteria provided, single submitter	clinical testing	The p.L452P variant (also known as c.1355T>C), located in coding exon 9 of the BRCA2 gene, results from a T to C substitution at nucleotide position 1355. The leucine at codon 452 is replaced by proline, an amino acid with similar properties. This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637781	SCV000759260	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 452 of the BRCA2 protein (p.Leu452Pro). This variant is present in population databases (rs753512842, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 225738). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000568425	SCV001358915	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 452 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/247608 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.
Sema4, Sema4	RCV000568425	SCV002533227	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568425	SCV003850026	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	RCV000211025	SCV004846909	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 452 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/247608 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, Department of Pathology, Netherlands Cancer Institute	RCV000766590	SCV002034339	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766590	SCV002038369	likely benign	not provided		no assertion criteria provided	clinical testing