Submissions for variant NM_000059.4(BRCA2):c.9377A>G (p.Gln3126Arg)

dbSNP: rs397507426

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165487	SCV000216218	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-13	criteria provided, single submitter	clinical testing	The p.Q3126R variant (also known as c.9377A>G), located in coding exon 24 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9377. The glutamine at codon 3126 is replaced by arginine, an amino acid with highly similar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly 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.
Counsyl	RCV000031817	SCV000786555	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707733	SCV000836842	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 3126 of the BRCA2 protein (p.Gln3126Arg). 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: 38234). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000031817	SCV002525956	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2022-02-10	criteria provided, single submitter	clinical testing	The BRCA2 c.9377A>G (p.Gln3126Arg) missense change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/ ). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has not been reported in women older than 70 years of age who have never had cancer ( https://whi.color.com ). To our knowledge, this variant has not been reported in individuals with hereditary breast and ovarian cancer or Fanconi anemia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporitng, PP3.
GeneDx	RCV002460893	SCV002756556	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 9605A>G; This variant is associated with the following publications: (PMID: 12228710)
Baylor Genetics	RCV003473231	SCV004211862	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165487	SCV004362811	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 3126 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 been reported in an individual affected with breast cancer (PMID: 32885271). This variant has not been identified 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.
All of Us Research Program, National Institutes of Health	RCV000031817	SCV004836361	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031817	SCV000054425	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-11-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358070	SCV001553718	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gln3126Arg variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC, ARUP Laboratories, Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs397507426) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases with uncertain significance by Ambry Genetics and Sharing Clinical Reports. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln3126 residue is conserved in in mammals but not in more distantly related organisms 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 variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (MaxEntScan and HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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.