Submissions for variant NM_000059.4(BRCA2):c.1447G>C (p.Ala483Pro)

dbSNP: rs80358432

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132314	SCV000187400	likely benign	Hereditary cancer-predisposing syndrome	2017-07-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001284409	SCV000516128	likely benign	not provided	2021-04-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20104584, 10923033, 26287763, 21520273)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417931	SCV000694538	likely benign	not specified	2020-07-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1447G>C (p.Ala483Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 244382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1447G>C has been reported in the literature in individuals affected with Breast Cancer (example, Borg_2010, Capanu_2012, Pal_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with the same pathogenic variant have been reported in the BIC database and at our laboratory respectively (BRCA2 c.8969G>A, p.Trp2990*), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. We have not ascertained any actionable evidence in over 4 years since its initial observation at our laboratory. Based on the emerging consensus evidence outlined above, the variant was re-classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284409	SCV001470194	uncertain significance	not provided	2024-08-07	criteria provided, single submitter	clinical testing	The BRCA2 c.1447G>C (p.Ala483Pro) variant has been reported in the published literature in individuals with breast cancer (PMID: 26287763 (2015), 21520273 (2011), 20104584 (2010)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001316342	SCV001506958	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 483 of the BRCA2 protein (p.Ala483Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 10923033, 20104584, 26287763). This variant is also known as c.1675G>C. ClinVar contains an entry for this variant (Variation ID: 51126). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132314	SCV003851395	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112923	SCV000145873	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112923	SCV000189295	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-01-21	no assertion criteria provided	clinical testing