Submissions for variant NM_000059.4(BRCA2):c.3709G>C (p.Ala1237Pro)

gnomAD frequency: 0.00001  dbSNP: rs398122770

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205458	SCV000261446	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-26	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 1237 of the BRCA2 protein (p.Ala1237Pro). This variant is not present in population databases (gnomAD no frequency). 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: 91806). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759605	SCV000889030	uncertain significance	not provided	2018-11-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776156	SCV000911188	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 1237 of the BRCA2 protein. Computational prediction 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). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007346). This variant has been identified in 1/249188 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.
Ambry Genetics	RCV000776156	SCV001182483	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.A1237P variant (also known as c.3709G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 3709. The alanine at codon 1237 is replaced by proline, an amino acid with highly similar properties. This amino acid position is well 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.
GeneDx	RCV000759605	SCV002005698	uncertain significance	not provided	2024-01-22	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; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3937G>C; This variant is associated with the following publications: (PMID: 32377563, 29884841, 9002670, 22193408)
Genetic Services Laboratory, University of Chicago	RCV001818243	SCV002070597	uncertain significance	not specified	2018-05-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000776156	SCV003846812	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	RCV000077714	SCV004845203	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 1237 of the BRCA2 protein. Computational prediction 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). 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 1/249188 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759605	SCV005877380	likely benign	not provided	2024-10-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077714	SCV000109517	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-24	no assertion criteria provided	clinical testing