Submissions for variant NM_000059.4(BRCA2):c.397C>T (p.Pro133Ser)

dbSNP: rs571823764

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530938	SCV000635324	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 133 of the BRCA2 protein (p.Pro133Ser). This variant is present in population databases (rs571823764, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462317). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284419	SCV001470209	uncertain significance	not provided	2020-07-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003584657	SCV004361168	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 133 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 BRCA2-related disorders in the literature, but has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007706). This variant has been identified in 1/250874 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.