Submissions for variant NM_000059.4(BRCA2):c.9425A>G (p.Asp3142Gly)

dbSNP: rs80359216

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657021	SCV000279317	uncertain significance	not provided	2024-02-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate cell viability and drug sensitivity comparable to wild type in mouse embryonic stem cells (PMID: 37922907); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9653A>G; This variant is associated with the following publications: (PMID: 19043619, 26269718, 31131967, 21533266, 31911673, 32377563, 29884841, 31853058, 33471991, 12228710, 21965345, 37922907)
Counsyl	RCV000083159	SCV000488828	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-06-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509927	SCV000607761	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	The p.D3142G variant (also known as c.9425A>G), located in coding exon 24 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9425. The aspartic acid at codon 3142 is replaced by glycine, an amino acid with similar properties. In one study, this variant was reported in 1/1345 ovarian cancer patients (Akbari MR et al. J Med Genet, 2011 Nov;48:783-6). Another study did not detect this variant in 60,466 breast cancer cases but it was detected in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000509927	SCV000689195	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 3142 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been analyzed by multifactorial analysis and classified as Uncertain (PMID: 31131967). This variant has been reported in 1 individual affected with ovarian cancer (PMID: 21965345). This variant has been identified in 2/31364 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657021	SCV001469730	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001295496	SCV001484421	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 3142 of the BRCA2 protein (p.Asp3142Gly). This variant is present in population databases (rs80359216, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 21965345). ClinVar contains an entry for this variant (Variation ID: 52834). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Sema4, Sema4	RCV000509927	SCV002532032	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004803941	SCV004846172	uncertain significance	BRCA2-related cancer predisposition	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 3142 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has reported that this variant does not impact BRCA2 function in growth and cisplatin and PARPi sensitivity assays in Brca2-deficient mouse embryonic stem cells (PMID: 37922907). This variant has been reported in an individual affected with ovarian cancer (PMID: 21965345) and it has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000457). Multifactorial analyses have reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and personal and family history of 1.0498 and 1.764, respectively (PMID: 31131967, 31853058). This variant has been identified in 2/31364 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.
Sharing Clinical Reports Project (SCRP)	RCV000083159	SCV000115233	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-06-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083159	SCV000147634	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000213617	SCV000592286	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp3142Gly variant was identified in 1 of 2690 proband chromosomes (frequency: 0.0004) from individuals or families with ovarian cancer (Akbari 2011). The variant was also identified in the following databases: dbSNP (ID: rs80359216) as "With Uncertain significance allele", ClinVar (7x, uncertain significance), LOVD 3.0 (1x, predicted neutral), UMD-LSDB (1x, unclassified variant), and the BIC Database (1x, clinical importance unknown). The variant was classified as a variant of uncertain significance by the Sharing Clinical Reports Project (SCRP) (derived from Myriad reports). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 2 of 30934 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 2 of 14986 chromosomes (freq: 0.0001); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. A study by Karchin 2008 utilizing bioinformatics predicted this variant to be neutral in its effect on protein function, with a protein likelihood ratio 0.059. Although the p.Asp3142 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the glycine variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.