Submissions for variant NM_000059.4(BRCA2):c.7051G>C (p.Ala2351Pro)

dbSNP: rs80358930

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195376	SCV000073142	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-29	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 2351 of the BRCA2 protein (p.Ala2351Pro). This variant is present in population databases (rs80358930, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28111427, 33629534). ClinVar contains an entry for this variant (Variation ID: 52257). 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 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.
Ambry Genetics	RCV000132200	SCV000187282	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The p.A2351P variant (also known as c.7051G>C), located in coding exon 13 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7051. The alanine at codon 2351 is replaced by proline, an amino acid with highly similar properties. This alteration has been detected in an individual from a Korean breast and/or ovarian cancer cohort (Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021). This alteration was also identified in an individual diagnosed with ovarian cancer (Sunar V et al. Asia Pac J Clin Oncol, 2022 Feb;18:84-92). 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. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000590253	SCV000210415	uncertain significance	not provided	2023-12-21	criteria provided, single submitter	clinical testing	Published functional studies suggest a neutral effect: demonstrated cell viability and drug sensitivity comparable to wild type (PMID: 37922907); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7279G>C; This variant is associated with the following publications: (PMID: 31131967, 33629534, 29255376, 28111427, 29884841, 36344258, 37020472, 36243179, 35534704, 37922907)
Counsyl	RCV000113697	SCV000488872	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001263511	SCV000695030	uncertain significance	not specified	2024-03-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7051G>C (p.Ala2351Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250694 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7051G>C has been reported in the literature with the protein level name (Ala2351Pro) in an individual susceptible to hereditary breast and ovarian cancer (Park_2017), in a patient affected with lung cancer (Klempner_2017), and in an epithelial ovarian cancer patient (Sundar_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29255376, 28111427, 33629534). ClinVar contains an entry for this variant (Variation ID: 52257). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590253	SCV000889123	uncertain significance	not provided	2020-11-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132200	SCV000906929	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 2351 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 ovarian cancer (PMID: 33629534) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0757 and 0.641, respectively (PMID: 31131967). This variant has been identified in 2/250694 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	RCV000590253	SCV002048428	uncertain significance	not provided	2021-07-16	criteria provided, single submitter	clinical testing	The BRCA2 c.7051G>C; p.Ala2351Pro variant (rs80358930) is reported in one individual with a clinical diagnosis of hereditary breast and/or ovarian cancer, but the variant was not determined to be causative (Park 2017). The variant is reported as a variant of uncertain significance by several sources in the ClinVar database (Variation ID: 52257). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 2351 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.462). Due to limited information, the clinical significance of the p.Ala2351Pro variant is uncertain at this time. References: Park JS et al. Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls. Cancer Res Treat. 2017 Oct;49(4):1012-1021. PMID: 28111427.
Mendelics	RCV001263511	SCV002517986	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113697	SCV004844356	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 2351 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 ovarian cancer (PMID: 33629534) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.0757 and 0.641, respectively (PMID: 31131967). This variant has been identified in 2/250694 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.
Baylor Genetics	RCV004566834	SCV005059109	uncertain significance	Familial cancer of breast	2024-01-11	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113697	SCV000147008	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing