Submissions for variant NM_000059.4(BRCA2):c.316G>A (p.Gly106Arg)

dbSNP: rs786201916

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164444	SCV000215084	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-03	criteria provided, single submitter	clinical testing	The p.G106R variant (also known as c.316G>A) located in coding exon 2 of the BRCA2 gene. This variant results from a G to A substitution at nucleotide position 316. The amino acid change results in glycine to arginine at codon 106, an amino acid with dissimilar properties. This change occurs in the last base pair of coding exon 2 which makes it likely to have some effect on normal mRNA splicing; however, predictions of potential splicing impact from two different computer models are conflicting. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 225000 alleles tested) in our clinical cohort (includes this individual). This amino acid position is well conserved in available vertebrate species, but this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.G106R remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637554	SCV000759018	uncertain significance	Hereditary breast ovarian cancer syndrome	2017-08-08	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 185084). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 106 of the BRCA2 protein (p.Gly106Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 3 of the BRCA2 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193279	SCV001362012	uncertain significance	not specified	2019-06-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.316G>A (p.Gly106Arg) 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. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249688 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.316G>A, has been reported in the literature in patients who were previously tested negative for a pathogenic BRCA1/2 mutation and had undergone retesting using multigene panels (Yadav_2017). The report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729420	SCV001976826	likely pathogenic	Fanconi anemia complementation group D1	2021-10-05	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
GeneDx	RCV003441762	SCV004169249	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: in vitro studies demonstrate partially aberrant splicing and partial rescue of cell survival, though the physiological relevance of a reduction (versus a complete loss) of BRCA2 is unknown (Tubeuf et al., 2020); Observed in individuals with Fanconi Anemia, including an individual with a pathogenic variant on the opposite allele (in trans) in published literature (Tubeuf et al., 2020; Radulovic et al., 2023); Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Yadav et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as 544G>A; This variant is associated with the following publications: (PMID: 31911673, 29884841, 32377563, 36721989, 32641407, 27878467, 31853058)