Submissions for variant NM_000059.4(BRCA2):c.9458G>C (p.Gly3153Ala)

gnomAD frequency: 0.00003  dbSNP: rs80359220

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045825	SCV000073838	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163366	SCV000213903	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	The p.G3153A variant (also known as c.9458G>C), located in coding exon 24 of the BRCA2 gene, results from a G to C substitution at nucleotide position 9458. The glycine at codon 3153 is replaced by alanine, an amino acid with similar properties. Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration is predicted to be neutral (Karchin R et al. Cancer Inform, 2008 Apr;6:203-16). This alteration was also classified as Likely Benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 Sep;40(9):1557-1578). This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with hyperdiploid ALL (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is poorly 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	RCV000588545	SCV000279319	likely benign	not provided	2019-04-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21702907, 19043619, 26580448)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818224	SCV000695241	uncertain significance	not specified	2025-02-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9458G>C (p.Gly3153Ala) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of 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 3.2e-05 in 251244 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9458G>C has been reported in the literature in at-least one family with breast and/or ovarian cancer and at-least one individual with hyperdiploid acute lymphoblastic leukemia, without strong evidence of causality (example: Zuntini_2018, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A functional study involving a combination of a mouse embryonic stem cell (mESC)-based assay using next-generation sequencing (NGS) and cell viability and drug sensitivity assays were used to evaluate the pathogenicity of the variant and the evidence suggested that the variant is functional (Biswas_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37922907, 26580448, 30254663). ClinVar contains an entry for this variant (Variation ID: 52841). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000114111	SCV000785178	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163366	SCV000903037	likely benign	Hereditary cancer-predisposing syndrome	2016-12-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588545	SCV001133982	uncertain significance	not provided	2024-05-28	criteria provided, single submitter	clinical testing	The BRCA2 c.9458G>C (p.Gly3153Ala) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 30254663 (2018)) and hyperdiploid acute lymphoblastic leukemia (PMID: 26580448 (2015)). This variant has also been reported in affected and reportedly healthy individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). It has also been detected as a somatic variant in metastatic pancreatic ductal adenocarcinoma (PDAC) (PMID: 31391296 (2020)). The frequency of this variant in the general population, 0.000054 (7/129016 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. This variant has been predicted to be likely benign based on computational and multifactorial analyses (PMIDs: 19043619 (2008), 31131967 (2019)). 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.
Mendelics	RCV000114111	SCV001139263	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818224	SCV002066735	uncertain significance	not specified	2020-12-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.9458G>C, in exon 25 that results in an amino acid change, p.Gly3153Ala. This sequence change does not appear to have been previously described in individuals with BRCA2-related disorders and has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP rs80359220). The p.Gly3153Ala change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Gly3153Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly3153Ala change remains unknown at this time.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000114111	SCV002526722	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-30	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: BP4
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114111	SCV000147642	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000114111	SCV000297579	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-11-18	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000114111	SCV004228301	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)