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	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 106 of the BRCA2 protein (p.Gly106Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs786201916, gnomAD 0.003%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 32641407, 36721989). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 185084). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 32641407). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 32641407). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055656	SCV001362012	likely pathogenic	Fanconi anemia	2024-11-18	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. As the variant alters the last conserved nucleotide of exon 3, adjacent to the canonical splice donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splicing donor site. One predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing demonstrating a partial level of out of frame exon 3 skipping in >60% of transcripts (Tubeuf_2020). The variant allele was found at a frequency of 4e-06 in 249688 control chromosomes. c.316G>A has been reported in the literature as a maternally inherited allele in a compound heterozygous genotype in at-least one individual affected with Fanconi Anemia (example, Radulovic_2023 cited in Tubeuf_2020). A maternal family history of breast cancer was reported although the extent of genotyping was not provided (Tubeuf_2020). The following publications have been ascertained in the context of this evaluation (PMID: 36721989, 32641407, 27878467). ClinVar contains an entry for this variant (Variation ID: 185084). Based on the evidence outlined above, the variant was classified as likely pathogenic for autosomal recessive Fanconi Anemia and Autosomal Dominant Herediatry Breast and Ovarian Cancer (HBOC).
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)