Submissions for variant NM_000059.4(BRCA2):c.9257G>C (p.Gly3086Ala)

dbSNP: rs574271678

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586031	SCV000293578	uncertain significance	not provided	2015-11-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9257G>C at the cDNA level, p.Gly3086Ala (G3086A) at the protein level, and results in the change of a Glycine to an Alanine (GGA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 9485G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly3086Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Gly3086Ala occurs at a position that is not conserved and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gly3086Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000144196	SCV000488053	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545556	SCV000635731	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580829	SCV000684044	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 3086 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). An RNA study has shown that this variant does not impact splicing (PMID: 29470806). A functional study has shown that this variant does not impact homology-directed DNA repair (PMID: 35736817). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 29470806). This variant has been identified in 20/249820 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002465535	SCV000695228	likely benign	not specified	2022-12-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9257G>C (p.Gly3086Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. This prediction is supported by a splicing assay showing that the variant resulted in a normal transcript (Wangensteen_2019). The variant allele was found at a frequency of 8e-05 in 249820 control chromosomes, predominantly at a frequency of 0.00066 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8e-05 vs 0.00075), allowing no conclusion about variant significance. c.9257G>C has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer without evidence of causality (Singh_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication reports experimental evidence evaluating an impact on HDR function (Hu_2022), showing a neutral effect. Five laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with four classifying it as uncertain significance and one benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000580829	SCV001180386	benign	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465535	SCV002760737	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492633	SCV004240377	uncertain significance	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000144196	SCV004846146	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 3086 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). An RNA study has shown that this variant does not impact splicing (PMID: 29470806). A functional study has shown that this variant does not impact homology-directed DNA repair (PMID: 35736817). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 29470806). This variant has been identified in 20/249820 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)	RCV000144196	SCV000189269	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236803	SCV000592271	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gly3086Ala variant was not identified in the literature nor was it identified in the Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, or the Zhejiang University database. The variant was identified in the following databases: dbSNP (ID: rs574271678) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Counsyl and four other submitters), COGR, and in LOVD 3.0 (1x). The variant was identified in control databases in 20 of 244720 chromosomes (1 homozygous) at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 20 of 30620 chromosomes (freq: 0.0007) but not in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Gly3086 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Gly3086Ala variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. 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.